142 results on '"van Hall T"'
Search Results
2. In vivo modelling of cutaneous T-cell lymphoma: the role of SOCS1
- Author
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Luo, Y, primary, Vermeer, MH, additional, De Gruijl, FR, additional, Zoutman, WH, additional, Sluijter, M, additional, Van Hall, T, additional, and Tensen, CP, additional
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- 2022
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3. Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma
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de Vos van Steenwijk, P. J., Ramwadhdoebe, T. H., Goedemans, R., Doorduijn, E. M., van Ham, J. J., Gorter, A., van Hall, T., Kuijjer, M. L., van Poelgeest, M. I.E., van der Burg, S. H., and Jordanova, E. S.
- Published
- 2013
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4. The structure of the TEIPP associated altered peptide ligand Trh4-p2ABU in complex with H-2D(b)
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Hafstrand, I., primary, Doorduijn, E., additional, Duru, A.D., additional, Buratto, J., additional, Oliveira, C.C., additional, Sandalova, T., additional, van Hall, T., additional, and Achour, A., additional
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- 2016
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5. The structure of the TEIPP associated Trh4 peptide in complex with H-2D(b)
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Hafstrand, I., primary, Doorduijn, E., additional, Duru, A.D., additional, Buratto, J., additional, Oliveira, C.C., additional, Sandalova, T., additional, van Hall, T., additional, and Achour, A., additional
- Published
- 2016
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6. Gain of chromosome 6 status does not influence HLA-expression in uveal melanoma
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VAN PELT, S, primary, VAN ESSEN, TH, additional, BRONKHORST, IHG, additional, VERSLUIS, M, additional, LUYTEN, GPM, additional, VAN HALL, T, additional, VAN DEN ELSEN, PJ, additional, VAN VELDEN, PA, additional, and JAGER, MJ, additional
- Published
- 2013
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7. An immunodominant CTL epitope expressed by in vitro transformed cells is derived from plasmid vector backbone sequences
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van Hall, T., primary, van de Rhee, N., additional, Schoenberger, S., additional, Vierboom, M., additional, Verreck, F., additional, Melief, C., additional, and Offringa, R., additional
- Published
- 1997
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8. Joint-Derived T Cells in Rheumatoid Arthritis Proliferate to Antigens Present in Autologous Synovial Fluid
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Maurice, M. M., primary, Res, P. C. M., additional, Leow, A., additional, van Hall, T., additional, Daha, M. R., additional, Struyk, L., additional, van den Elsen, P., additional, Breedveld, F. C., additional, and Verweij, C. L., additional
- Published
- 1995
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9. Immunity Unchained: Improving Cancer Immunotherapy by targeti ng the Tumor Macro-Environment
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Dammeijer, Floris, Aerts, Joachim, Hendriks, Rudi, van Hall, T, and Pulmonary Medicine
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SDG 3 - Good Health and Well-being - Published
- 2021
10. BioIns-O-17 - In vivo modelling of cutaneous T-cell lymphoma: the role of SOCS1.
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Luo, Y, Vermeer, MH, De Gruijl, FR, Zoutman, WH, Sluijter, M, Van Hall, T, and Tensen, CP
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IN vivo studies , *CUTANEOUS T-cell lymphoma , *CARRIER proteins , *CANCER patient medical care - Published
- 2022
- Full Text
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11. The urgent need to recover MHC class I in cancers for effective immunotherapy
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Angel M Garcia Lora, Elien M. Doorduijn, Natalia Aptsiauri, Federico Garrido, Thorbald van Hall, [Garrido,F] Departamento de Bioquimica, Biologia Molecular III e Inmunologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. [Garrido,F] Aptsiauri,N, Garcia Lora,AM] Servicio de Análisis Clínicos, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Garrido,F] Aptsiauri,N, Garcia Lora,AM] Instituto de Investigacion Biosanitaria de Granada (IBS.Granada), Granada, Spain. [Doorduijn,E, van Hall,T] Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands., and This work was supported by grants co-financed by FEDER funds (EU) from the Instituto de Salud Carlos III (CP03/0111, PI12/02031, PI 08/1265, PI 11/01022, PI11/01386, PI14/01978, PI15/00528, RETIC RD 06/020, RD09/0076/00165, PT13/0010/0039), Junta de Andalucía in Spain (Group CTS-143, and CTS-695, CTS-3952, CVI-4740 and PI 09/0382 grant), Worldwide Cancer Research15-1166 grant, and by Dutch Cancer Society (UL 2010-4785, TvH).
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Phenomena and Processes::Immune System Phenomena::Immune System Processes::Tumor Escape [Medical Subject Headings] ,Presentación de antígeno ,Genes clase I del complejo de histocompatibilidad (MHC) ,medicine.medical_treatment ,Immunology ,Cell ,chemical and pharmacologic phenomena ,Escape del tumor ,Phenomena and Processes::Immune System Phenomena::Immune System Processes::Antigen Presentation [Medical Subject Headings] ,Article ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Downregulation and upregulation ,Cancer immunotherapy ,Neoplasms ,Regulación hacia arriba ,MHC class I ,medicine ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [Medical Subject Headings] ,Animals ,Humans ,Immunology and Allergy ,Inmunoterapia ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings] ,biology ,MHC class I antigen ,Histocompatibility Antigens Class I ,Immunotherapy ,Linfocitos T ,Diseases::Neoplasms [Medical Subject Headings] ,Neoplasias ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Histocompatibility Antigens Class I [Medical Subject Headings] ,Humanos ,medicine.anatomical_structure ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Up-Regulation [Medical Subject Headings] ,030220 oncology & carcinogenesis ,biology.protein ,Antígenos de histocompatibilidad clase I ,Antibody ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Major Histocompatibility Complex::Genes, MHC Class I [Medical Subject Headings] ,030215 immunology - Abstract
We would like to thank Dr M Bernal who has helped us in preparing the figure for the manuscript. This work was supported by grants co-financed by FEDER funds (EU) from the Instituto de Salud Carlos III (CP03/0111, PI12/02031, PI 08/1265, PI 11/01022, PI11/01386, PI14/01978, PI15/00528, RETIC RD 06/020, RD09/0076/00165, PT13/0010/0039), Junta de Andalucia in Spain (Group CTS-143, and CTS-695, CTS-3952, CVI-4740 and PI 09/0382 grant), Worldwide Cancer Research 15-1166 grant, and by Dutch Cancer Society (UL 2010-4785, TvH)., Immune escape strategies aimed to avoid T-cell recognition, including the loss of tumor MHC class I expression, are commonly found in malignant cells. Tumor immune escape has proven to have a negative effect on the clinical outcome of cancer immunotherapy, including treatment with antibodies blocking immune checkpoint molecules. Hence, there is an urgent need to develop novel approaches to overcome tumor immune evasion. MHC class I antigen presentation is often affected in human cancers and the capacity to induce upregulation of MHC class I cell surface expression is a critical step in the induction of tumor rejection. This review focuses on characterization of rejection, escape, and dormant profiles of tumors and its microenvironment with a special emphasis on the tumor MHC class I expression. We also discuss possible approaches to recover MHC class I expression on tumor cells harboring reversible/‘soft’ or irreversible/‘hard’ genetic lesions. Such MHC class I recovery approaches might well synergize with complementary forms of immunotherapy., FEDER funds (EU) from the Instituto de Salud Carlos III CP03/0111 PI12/02031 PI 08/1265 PI 11/01022 PI11/01386 PI14/01978 PI15/00528 RETIC RD 06/020 RD09/0076/00165 PT13/0010/0039, Junta de Andalucía CTS-143 CTS-695 CTS-3952 CVI-4740 PI 09/0382, Worldwide Cancer Research 15-1166, KWF Kankerbestrijding UL 2010-4785
- Published
- 2016
12. Studies on local APC and HPV-specific T cells as prelude to the immunotherapy of human tumors
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Heusinkveld, M., van der Burg, S.H., Kenter, G.G., van Hall, T., Welters, M.J.P., Burg, S.H. van der, Hall, T. van, Leiden University, Kenter, Gemma, and CCA - Oncogenesis
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HPV16 ,Oropharyngeal cancer ,Tumor associated macrophages ,M2 macrophages ,Cetuximab ,PGE2 - Abstract
In this thesis, several aspects and cellular players involved in the immune response to (HPV-induced) tumors were investigated. In chapter 2 a detailed analysis of HPV-specific immunity in a large group of patients with HPV-induced cervical cancer (CxCa) in relation to HLA-types and prognostic factors was performed. In 30% of the tested patients, circulating HPV specific T cells were found, most often in patients with deeply infiltrating tumors. In this group, patients with HPV specific proliferative immunity displayed better disease free survival. It was shown earlier by Piersma et al [69] that only in 30% of TIL populations, HPV specific T cells were found. In chapter 3 an in depth analysis of the breadth and type of HPV specific T-cell populations in tumor infiltrating T cell (TIL) cultures or LN cells from HPV 16 or 18 positive CxCa patients was performed. We found that if patients displayed a HPV-specific T cell response, this was surprisingly broad. Despite recognition, a number of cells did not produce type 1 cytokines and therefore we tested what TLR-agonist was able to support cytokine induction by these T cells. In chapter 4 we asked the question whether HPV-specific T cells play a role in HPV-induced HNSCC. We hypothesize that HPV-induced tumors are more immunogenic and stimulate strong T-cell reactivity to the viral oncoproteins in contrast to HPV-negative tumors. We set up a pilot study to investigate whether HPV is present in HNSCC in the Dutch patient population and at which anatomical site. Accordingly, blood and tumor infiltrating T cells were analyzed for the presence of functional HPV specific T cells. The lack of T cell responses in CxCa patients and the __poised__ function of tumor-antigen specific T cells could be a lack of proper priming by DC. Therefore we investigated in chapter 5A the effects of CxCa produced soluble factors on the differentiation of antigen presenting cells (APC). Several tumor cell lines hampered DC differentiation or even skewed monocyte differentiation into tolerogenic tumor promoting M2 macrophages. We identified the factors responsible for this and investigated the outcome of the interaction of HPV specific T-cell clones with these macrophages. Since patients with advanced or recurrent disease are treated with platinum based chemotherapy we investigated the immune-modulating effect of this therapy on tumor cells, tumor-modulated APC and subsequent interaction with T cells. This ongoing work is summarized in chapter 5B. Therapeutic vaccination is being developed for treatment of chronic infections and cancer, and aims to generate protective T-cell immunity. Although some clinical successes have been reported, particularly in the field of cancer vaccination, there is still much to be gained in terms of efficacy [91,92]. Especially the adjuvant used and the route of administration of vaccines are critical factors that determine the type and memory of the resulting T-cell response. Intradermal vaccination is an attractive method for diseases in the skin such as HPV induced tumors and melanomas since the induced T cells get skin-homing instructions. In chapter 5 we showed already that highly pure DC can become activated by the addition of several different TLR agonists in vitro. To assess the effect of these TLR agonists on the APC present in the dermis, a human skin-explant model was used to analyze the phenotype and function of the APC migrating out the skin upon TLR-injection. These results are described in chapter 6. Surprisingly, only few TLR-agonists turned out to induce activation of the migrating cells. The current treatment of patients with advanced colorectal cancer consists of chemotherapy together with the MAb bevacizumab that blocks soluble VEGF. The addition of a second antibody that targets tumor expressed EGFR (cetuximab) to this treatment did not result in the expected disease free survival benefit in a large randomized phase III study (CAIROII). Analysis of gene polymorphisms in the Fc__Receptors revealed that patients with the high affinity FCGR3A polymorphism did significantly worse upon addition of cetuximab to the standard treatment. As colon cancers are generally infiltrated with macrophages we tested the hypothesis that membrane bound antibodies could activate tumor promoting M2 macrophages and that this would happen more efficiently in patients with high affinity FCGRIIIA in chapter 7. In chapter 8 the work of this thesis is discussed in light of recent literature.
- Published
- 2012
13. Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy.
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van Elsas MJ, Middelburg J, Labrie C, Roelands J, Schaap G, Sluijter M, Tonea R, Ovcinnikovs V, Lloyd K, Schuurman J, Riesenfeld SJ, Gajewski TF, de Miranda NFCC, van Hall T, and van der Burg SH
- Subjects
- Animals, Mice, Humans, Receptors, CCR5 metabolism, Receptors, CCR5 genetics, Mice, Inbred C57BL, Macrophage Activation immunology, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Lymphocyte Activation immunology, Female, Tumor Microenvironment immunology, CD8-Positive T-Lymphocytes immunology, Immunotherapy methods, Macrophages immunology
- Abstract
Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8
+ T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8+ T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling. Exposure of non-polarized macrophages to activated T cell supernatant and tumor lysate recapitulates the late-stage activated and tumoricidal phenotype in vitro. The transcriptomic signature of these macrophages is also detected in a similar macrophage population present in human tumors and coincides with clinical response to immune checkpoint inhibitors. The requirement of a functional co-operation between CD8+ T cells and effector macrophages for effective immunotherapy gives warning to combinations with broad macrophage-targeting strategies., Competing Interests: Declaration of interests V.O., K.L., and J.S. are (former) employees of Genmab and have ownership interests (including stock, patents, warrants, etc.). J.M., V.O., K.L., J.S., and T.v.H. are inventors on a patent (WO2022049220A2) involving the combination of CD3 bsAb therapy in combination with vaccination., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
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14. Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell-Based Immunotherapies.
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Groeneveldt C, Kinderman P, Griffioen L, Rensing O, Labrie C, van den Wollenberg DJM, Hoeben RC, Coffey M, Loghmani H, Verdegaal EME, Welters MJP, van der Burg SH, van Hall T, and van Montfoort N
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- Humans, Animals, Mice, Antibodies, Neutralizing, Antibodies, Viral, T-Lymphocytes, Immunotherapy, Oncolytic Virotherapy, Oncolytic Viruses, Reoviridae, Neoplasms therapy, Neoplasms etiology
- Abstract
Reovirus type 3 Dearing (Reo), manufactured for clinical application as pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Because most people have been preexposed to Reo, neutralizing antibodies (NAb) are prevalent in patients with cancer and might present a barrier to effective Reo therapy. Here, we tested serum of patients with cancer and healthy controls (n = 100) and confirmed that Reo NAbs are present in >80% of individuals. To investigate the effect of NAbs on both the oncolytic and the immunostimulatory efficacy of Reo, we established an experimental mouse model with Reo preexposure. The presence of preexposure-induced NAbs reduced Reo tumor infection and prevented Reo-mediated control of tumor growth after intratumoral Reo administration. In B cell-deficient mice, the lack of NAbs provided enhanced tumor growth control after Reo monotherapy, indicating that NAbs limit the oncolytic capacity of Reo. In immunocompetent mice, intratumoral T-cell influx was not affected by the presence of preexposure-induced NAbs and consequently, combinatorial immunotherapy strategies comprising Reo and T-cell engagers or checkpoint inhibitors remained effective in these settings, also after a clinically applied regimen of multiple intravenous pelareorep administrations. Altogether, our data indicate that NAbs hamper the oncolytic efficacy of Reo, but not its immunotherapeutic capacity. Given the high prevalence of seropositivity for Reo in patients with cancer, our data strongly advocate for the application of Reo as part of T cell-based immunotherapeutic strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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15. T-cell stimulating vaccines empower CD3 bispecific antibody therapy in solid tumors.
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Middelburg J, Sluijter M, Schaap G, Göynük B, Lloyd K, Ovcinnikovs V, Zom GG, Marijnissen RJ, Groeneveldt C, Griffioen L, Sandker GGW, Heskamp S, van der Burg SH, Arakelian T, Ossendorp F, Arens R, Schuurman J, Kemper K, and van Hall T
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- Male, Animals, Mice, T-Lymphocytes, CD3 Complex, Antigens, Neoplasm, Tumor Microenvironment, Neoplasms drug therapy, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Vaccines
- Abstract
CD3 bispecific antibody (CD3 bsAb) therapy is clinically approved for refractory hematological malignancies, but responses in solid tumors have been limited so far. One of the main hurdles in solid tumors is the lack of sufficient T-cell infiltrate. Here, we show that pre-treatment vaccination, even when composed of tumor-unrelated antigens, induces CXCR3-mediated T-cell influx in immunologically 'cold' tumor models in male mice. In the absence of CD3 bsAb, the infiltrate is confined to the tumor invasive margin, whereas subsequent CD3 bsAb administration induces infiltration of activated effector CD8 T cells into the tumor cell nests. This combination therapy installs a broadly inflamed Th1-type tumor microenvironment, resulting in effective tumor eradication. Multiple vaccination formulations, including synthetic long peptides and viruses, empower CD3 bsAb therapy. Our results imply that eliciting tumor infiltration with vaccine-induced tumor-(un)related T cells can greatly improve the efficacy of CD3 bsAbs in solid tumors., (© 2024. The Author(s).)
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- 2024
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16. Tumor Pigmentation Does Not Affect Light-Activated Belzupacap Sarotalocan Treatment but Influences Macrophage Polarization in a Murine Melanoma Model.
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Ma S, Huis In't Veld RV, Hao Y, Gu Z, Rich C, Gelmi MC, Mulder AA, van Veelen PA, Vu TKH, van Hall T, Ossendorp FA, and Jager MJ
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- Animals, Mice, Monophenol Monooxygenase metabolism, Mice, Inbred C57BL, Macrophages metabolism, Pigmentation, Melanoma genetics
- Abstract
Purpose: Pigmentation in uveal melanoma is associated with increased malignancy and is known as a barrier for photodynamic therapy. We investigated the role of pigmentation in tumor behavior and the response to light-activated Belzupacap sarotalocan (Bel-sar) treatment in a pigmented (wild type) and nonpigmented (tyrosinase knock-out [TYR knock-out]) cell line in vitro and in a murine model., Methods: The B16F10 (TYR knock-out) was developed using CRISPR/Cas9. After the treatment with light-activated Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were measured by flow cytometry. Treated tumor cells were co-cultured with bone marrow-derived macrophages (BMDMs) and dendritic cells (DCs) to assess phagocytosis and activation. Both cell lines were injected subcutaneously in syngeneic C57BL/6 mice., Results: Knock-out of the tyrosinase gene in B16F10 led to loss of pigmentation and immature melanosomes. Pigmented tumors contained more M1 and fewer M2 macrophages compared with amelanotic tumors. Bel-sar treatment induced near complete cell death, accompanied with enhanced exposure of DAMPs in both cell lines, resulting in enhanced phagocytosis of BMDMs and maturation of DCs. Bel-sar treatment induced a shift to M1 macrophages and delayed tumor growth in both in vivo tumor models. Following treatment, especially the pigmented tumors and their draining lymph nodes contained IFN-gamma positive CD8+T cells., Conclusions: Pigmentation influenced the type of infiltrating macrophages in the tumor, with more M1 macrophages in pigmented tumors. Belzupacap sarotalocan treatment induced immunogenic cell death and tumor growth delay in pigmented as well as in nonpigmented models and stimulated M1 macrophage influx in both models.
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- 2024
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17. The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent.
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Middelburg J, Ghaffari S, Schoufour TAW, Sluijter M, Schaap G, Göynük B, Sala BM, Al-Tamimi L, Scheeren F, Franken KLMC, Akkermans JJLL, Cabukusta B, Joosten SA, Derksen I, Neefjes J, van der Burg SH, Achour A, Wijdeven RHM, Weidanz J, and van Hall T
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- Mice, Animals, Leukocyte Immunoglobulin-like Receptor B1 metabolism, Killer Cells, Natural, Ligands, Peptides metabolism, NK Cell Lectin-Like Receptor Subfamily C metabolism, Histocompatibility Antigens Class I metabolism, Neoplasms metabolism
- Abstract
The immune checkpoint NKG2A/CD94 is a promising target for cancer immunotherapy, and its ligand major histocompatibility complex E (MHC-E) is frequently upregulated in cancer. NKG2A/CD94-mediated inhibition of lymphocytes depends on the presence of specific leader peptides in MHC-E, but when and where they are presented in situ is unknown. We apply a nanobody specific for the Qdm/Qa-1
b complex, the NKG2A/CD94 ligand in mouse, and find that presentation of Qdm peptide depends on every member of the endoplasmic reticulum-resident peptide loading complex. With a turnover rate of 30 min, the Qdm peptide reflects antigen processing capacity in real time. Remarkably, Qdm/Qa-1b complexes require inflammatory signals for surface expression in situ, despite the broad presence of Qa-1b molecules in homeostasis. Furthermore, we identify LILRB1 as a functional inhibition receptor for MHC-E in steady state. These data provide a molecular understanding of NKG2A blockade in immunotherapy and assign MHC-E as a convergent ligand for multiple immune checkpoints., Competing Interests: Declaration of interests J.W. was co-founder and chief scientist at Abexxa Biologics, Inc., during the study and had ownership interest (including stock and patents) of Abexxa. J.W. is a consultant for Boehringer-Ingelheim International GmbH. T.v.H. reports receiving a commercial grant from Abexxa and was an advisory board member for the same., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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18. Longitudinal evaluation of the biodistribution and cellular internalization of the bispecific CD3xTRP1 antibody in syngeneic mouse tumor models.
- Author
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Sandker GGW, Middelburg J, Wilbrink E, Molkenboer-Kuenen J, Aarntzen E, van Hall T, and Heskamp S
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- Male, Mice, Animals, CD8-Positive T-Lymphocytes, Tissue Distribution, CD3 Complex, Mice, Inbred C57BL, Antigens, Neoplasm, Disease Models, Animal, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Neoplasms
- Abstract
Background: CD3 bispecific antibodies (CD3-bsAbs) require binding of both a tumor-associated surface antigen and CD3 for their immunotherapeutic effect. Their efficacy is, therefore, influenced by the tumor uptake and the extracellular dose. To optimize their currently limited efficacy in solid tumors, increased understanding of their pharmacokinetics and in vivo internalization is needed., Methods: Here, were studied the pharmacokinetics and in vivo internalization of CD3xTRP1, a fully murine Fc-inert bsAb, in endogenous TRP1-expressing immunocompetent male C57BL/6J mice bearing TRP1-positive and negative tumors over time. Matching bsAbs lacking TRP1-binding or CD3-binding capacity served as controls. BsAbs were radiolabeled with
111 In to investigate their pharmacokinetics, target binding, and biodistribution through SPECT/CT imaging and ex vivo biodistribution analyses. Co-injection of111 In- and125 I-labeled bsAb was performed to investigate the in vivo internalization by comparing tissue concentrations of cellular residing111 In versus effluxing125 I. Antitumor therapy effects were evaluated by monitoring tumor growth and immunohistochemistry., Results: SPECT/CT and biodistribution analyses showed that CD3xTRP1 specifically targeted TRP1-positive tumors and CD3-rich lymphoid organ and uptake peaked 24 hours pi (KPC3-TRP1: 37.7%ID/g±5.3%ID/g, spleen: 29.0%ID/g±3.9%ID/g). Studies with control bsAbs demonstrated that uptake of CD3xTRP1 in TRP1-positive tumors and CD3-rich tissues was primarily receptor-mediated. Together with CD3xTRP1 in the circulation being mainly unattached, this indicates that CD3+ T cells are generally not traffickers of CD3-bsAbs to the tumor. Additionally, target-mediated clearance by TRP1-expressing melanocytes was not observed. We further demonstrated rapid internalization of CD3xTRP1 in KPC3-TRP1 tumors (24 hours pi: 54.9%±2.3% internalized) and CD3-rich tissues (spleen, 24 hours pi: 79.7%±0.9% internalized). Therapeutic effects by CD3xTRP1 were observed for TRP1-positive tumors and consisted of high tumor influx of CD8+ T cells and neutrophils, which corresponded with increased necrosis and growth delay., Conclusions: We show that CD3xTRP1 efficiently targets TRP1-positive tumors and CD3-rich tissues primarily through receptor-mediated targeting. We further demonstrate rapid receptor-mediated internalization of CD3xTRP1 in TRP1-positive tumors and CD3-rich tissues. Even though this significantly decreases the therapeutical available dose, CD3xTRP1 still induced effective antitumor T-cell responses and inhibited tumor growth. Together, our data on the pharmacokinetics and mechanism of action of CD3xTRP1 pave the way for further optimization of CD3-bsAb therapies., Competing Interests: Competing interests: TVH received a research grant from Genmab. Bispecific antibodies were provided by Genmab. TVH and JM are authors on a patent involving the combination of CD3-bsAb therapy in combination with vaccination. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2023
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19. Socs1-knockout in skin-resident CD4 + T cells in a protracted contact-allergic reaction results in an autonomous skin inflammation with features of early-stage mycosis fungoides.
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Luo Y, Vermeer MH, de Haan S, Kinderman P, de Gruijl FR, van Hall T, and Tensen CP
- Abstract
Recent detailed genomic analysis of mycosis fungoides (MF) identified suppressor of cytokine signaling 1 (SOCS1), an inhibitor of JAK/STAT signaling, as one of the frequently deleted tumor suppressors in MF, and one-copy deletion of SOCS1 was confirmed in early-stage MF lesions. To better understand the functional role of SOCS1 in the genesis of MF, we used a genetically engineered mouse model emulating heterozygous SOCS1 loss in skin resident CD4
+ T cells. In these mice an experimentally induced contact-allergic reaction was maintained for 20 weeks. Ten weeks after discontinuing contact-allergic challenges, only the skin with locally one-copy deletion of Socs1 in CD4+ T cells still showed high numbers of CD3+ /CD4+ Socs1 k.o. cells in the dermis (p < 0.0001) with prevalent Stat3 activation (p <0.001). And in one out of 9 mice, this had progressed to far more dramatic increases, including the thickened epidermis, and with an explosive growth of Socs1 k.o. T cells in circulation; indicative of cutaneous lymphoma. Hence, we show that Socs1 mono-allelic loss in CD4+ T cells locally in protractedly inflamed skin results in autonomous skin inflammation with features of early-stage MF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)- Published
- 2023
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20. PD-L1 checkpoint blockade promotes regulatory T cell activity that underlies therapy resistance.
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van Gulijk M, van Krimpen A, Schetters S, Eterman M, van Elsas M, Mankor J, Klaase L, de Bruijn M, van Nimwegen M, van Tienhoven T, van Ijcken W, Boon L, van der Schoot J, Verdoes M, Scheeren F, van der Burg SH, Lambrecht BN, Stadhouders R, Dammeijer F, Aerts J, and van Hall T
- Subjects
- Humans, Mice, Animals, T-Lymphocytes, Regulatory, B7-H1 Antigen, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Skin Neoplasms
- Abstract
Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood. Here, we identified preferential activation and enhanced suppressive capacity of regulatory T cells (T
reg cells) in αPD-L1 therapy-resistant solid tumor-bearing mice. Treg cell depletion reversed resistance to αPD-L1 with concomitant expansion of effector T cells. Moreover, we found that tumor-infiltrating Treg cells in human patients with skin cancer, and in patients with non-small cell lung cancer, up-regulated a suppressive transcriptional gene program after ICB treatment, which correlated with lack of treatment response. αPD-1/PD-L1-induced PD-1+ Treg cell activation was also seen in peripheral blood of patients with lung cancer and mesothelioma, especially in nonresponders. Together, these data reveal that treatment with αPD-1 and αPD-L1 unleashes the immunosuppressive role of Treg cells, resulting in therapy resistance, suggesting that Treg cell targeting is an important adjunct strategy to enhance therapeutic efficacy.- Published
- 2023
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21. Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy.
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van Elsas MJ, Labrie C, Etzerodt A, Charoentong P, van Stigt Thans JJC, Van Hall T, and van der Burg SH
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- Animals, Mice, Humans, Immunotherapy methods, Macrophages, Tumor Microenvironment, T-Lymphocytes, Neoplasms pathology
- Abstract
Background: Primary and secondary resistance is a major hurdle in cancer immunotherapy. Therefore, a better understanding of the underlying mechanisms involved in immunotherapy resistance is of pivotal importance to improve therapy outcome., Method: Here, two mouse models with resistance against therapeutic vaccine-induced tumor regression were studied. Exploration of the tumor microenvironment by high dimensional flow cytometry in combination with therapeutic in vivo settings allowed for the identification of immunological factors driving immunotherapy resistance., Results: Comparison of the tumor immune infiltrate during early and late regression revealed a change from tumor-rejecting toward tumor-promoting macrophages. In concert, a rapid exhaustion of tumor-infiltrating T cells was observed. Perturbation studies identified a small but discernible CD163
hi macrophage population, with high expression of several tumor-promoting macrophage markers and a functional anti-inflammatory transcriptome profile, but not other macrophages, to be responsible. In-depth analyses revealed that they localize at the tumor invasive margins and are more resistant to Csf1r inhibition when compared with other macrophages. In vivo studies validated the activity of heme oxygenase-1 as an underlying mechanism of immunotherapy resistance. The transcriptomic profile of CD163hi macrophages is highly similar to a human monocyte/macrophage population, indicating that they represent a target to improve immunotherapy efficacy., Conclusions: In this study, a small population of CD163hi tissue-resident macrophages is identified to be responsible for primary and secondary resistance against T-cell-based immunotherapies. While these CD163hi M2 macrophages are resistant to Csf1r-targeted therapies, in-depth characterization and identification of the underlying mechanisms driving immunotherapy resistance allows the specific targeting of this subset of macrophages, thereby creating new opportunities for therapeutic intervention with the aim to overcome immunotherapy resistance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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22. Thermal-exchange HLA-E multimers reveal specificity in HLA-E and NKG2A/CD94 complex interactions.
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Ruibal P, Derksen I, van Wolfswinkel M, Voogd L, Franken KLMC, El Hebieshy AF, van Hall T, Schoufour TAW, Wijdeven RH, Ottenhoff THM, Scheeren FA, and Joosten SA
- Subjects
- Protein Binding, Peptides, Receptors, Antigen, T-Cell, NK Cell Lectin-Like Receptor Subfamily D chemistry, NK Cell Lectin-Like Receptor Subfamily D metabolism, NK Cell Lectin-Like Receptor Subfamily C, HLA-E Antigens, Killer Cells, Natural, Histocompatibility Antigens Class I metabolism
- Abstract
There is growing interest in HLA-E-restricted T-cell responses as a possible novel, highly conserved, vaccination targets in the context of infectious and malignant diseases. The developing field of HLA multimers for the detection and study of peptide-specific T cells has allowed the in-depth study of TCR repertoires and molecular requirements for efficient antigen presentation and T-cell activation. In this study, we developed a method for efficient peptide thermal exchange on HLA-E monomers and multimers allowing the high-throughput production of HLA-E multimers. We optimized the thermal-mediated peptide exchange, and flow cytometry staining conditions for the detection of TCR and NKG2A/CD94 receptors, showing that this novel approach can be used for high-throughput identification and analysis of HLA-E-binding peptides which could be involved in T-cell and NK cell-mediated immune responses. Importantly, our analysis of NKG2A/CD94 interaction in the presence of modified peptides led to new molecular insights governing the interaction of HLA-E with this receptor. In particular, our results reveal that interactions of HLA-E with NKG2A/CD94 and the TCR involve different residues. Altogether, we present a novel HLA-E multimer technology based on thermal-mediated peptide exchange allowing us to investigate the molecular requirements for HLA-E/peptide interaction with its receptors., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)
- Published
- 2023
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23. Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy.
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Groeneveldt C, van Ginkel JQ, Kinderman P, Sluijter M, Griffioen L, Labrie C, van den Wollenberg DJM, Hoeben RC, van der Burg SH, Ten Dijke P, Hawinkels LJAC, van Hall T, and van Montfoort N
- Subjects
- Mice, Animals, CD8-Positive T-Lymphocytes, Transforming Growth Factor beta, Immunotherapy, Tumor Microenvironment, Pancreatic Neoplasms drug therapy, Colonic Neoplasms
- Abstract
The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8
+ T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-β signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteristics. Here, we investigated the effect of TGF-β blockade on the antitumor efficacy of Reo&CD3-bsAb therapy in the preclinical pancreatic KPC3 and colon MC38 tumor models, where TGF-β signaling is active. TGF-β blockade impaired tumor growth in both KPC3 and MC38 tumors. Furthermore, TGF-β blockade did not affect reovirus replication in both models and significantly enhanced the Reo-induced T-cell influx in MC38 colon tumors. Reo administration decreased TGF-β signaling in MC38 tumors but instead increased TGF-β activity in KPC3 tumors, resulting in the accumulation of α-smooth muscle actin (αSMA+ ) fibroblasts. In KPC3 tumors, TGF-β blockade antagonized the antitumor effect of Reo&CD3-bsAb therapy, even though T-cell influx and activity were not impaired. Moreover, genetic loss of TGF-β signaling in CD8+ T cells had no effect on therapeutic responses. In contrast, TGF-β blockade significantly improved therapeutic efficacy of Reo&CD3-bsAb in mice bearing MC38 colon tumors, resulting in a 100% complete response. Further understanding of the factors that determine this intertumor dichotomy is required before TGF-β inhibition can be exploited as part of viroimmunotherapeutic combination strategies to improve their clinical benefit., Significance: Blockade of the pleiotropic molecule TGF-β can both improve and impair the efficacy of viro-immunotherapy, depending on the tumor model. While TGF-β blockade antagonized Reo&CD3-bsAb combination therapy in the KPC3 model for pancreatic cancer, it resulted in 100% complete responses in the MC38 colon model. Understanding factors underlying this contrast is required to guide therapeutic application., (© 2023 The Authors; Published by the American Association for Cancer Research.)- Published
- 2023
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24. In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1.
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Luo Y, Vermeer MH, de Gruijl FR, Zoutman WH, Sluijter M, van Hall T, and Tensen CP
- Abstract
Introduction: Mycosis fungoides (MF), the most common type of Cutaneous T cell Lymphoma (CTCL), is characterized by an inflamed skin intermixed with proliferating malignant mature skin-homing CD4+ T cells. Detailed genomic analyses of MF skin biopsies revealed several candidate genes possibly involved in genesis of these tumors and/or potential targets for therapy. These studies showed, in addition to common loss of cell cycle regulator CDKN2A, activation of several oncogenic pathways, most prominently and consistently involving JAK/STAT signaling. SOCS1, an endogenous inhibitor of the JAK/STAT signaling pathway, was identified as a recurrently deleted gene in MF, already occurring in the earliest stages of the disease., Methods: To explore the mechanisms of MF, we create in vivo mouse models of autochthonous CTCLs and these genetically engineered mouse models (GEMMS) can also serve as valid experimental models for targeted therapy. We describe the impact of allelic deletion of Socs1 in CD4 T cells of the skin. To achieve this, we crossed inducible Cre-transgenic mice in the CD4 lineage with transgenic mice carrying floxed genes of Socs1 . We first determined optimal conditions for Socs1 ablation with limited effects on circulating CD4 T-cells in blood. Next, we started time-course experiments mimicking sustained inflammation, typical in CTCL. FACS analysis of the blood was done every week. Skin biopsies were analyzed by immunocytochemical staining at the end of the experiment., Results: We found that the Socs1 knockout transgenic group had thicker epidermis of treated skin compared with the control group and had more CD3 and CD4 in the skin of the transgenic group compared to the control group. We also noted more activation of Stat3 by staining for P-Stat3 in Socs1 knockout compared to wt CD4+T cells in the skin. The results also indicated that single copy loss of Socs1 in combination with sustained inflammation is insufficient to start a phenotype resembling early stage mycosis fungoides within eight weeks in these mice., Conclusion: In sum, we developed and optimized an autochthonous murine model permitting selective knockout of Socs1 in skin infiltrating CD4 T-cells. This paves the way for more elaborate experiments to gain insight in the oncogenesis of CTCL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luo, Vermeer, de Gruijl, Zoutman, Sluijter, van Hall and Tensen.)
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- 2022
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25. Targeting pancreatic cancer by TAK-981: a SUMOylation inhibitor that activates the immune system and blocks cancer cell cycle progression in a preclinical model.
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Kumar S, Schoonderwoerd MJA, Kroonen JS, de Graaf IJ, Sluijter M, Ruano D, González-Prieto R, Verlaan-de Vries M, Rip J, Arens R, de Miranda NFCC, Hawinkels LJAC, van Hall T, and Vertegaal ACO
- Subjects
- Animals, Cell Cycle, Cell Proliferation, Interferons, Killer Cells, Natural, Mice, Sumoylation, Tumor Microenvironment, Ubiquitin-Activating Enzymes, Ubiquitins metabolism, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms pathology
- Abstract
Objective: Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC., Design: We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981., Results: We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared with normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumour burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and natural killer (NK) cells but transiently decreased B cell numbers in tumour, peripheral blood, spleen and lymph nodes. Single cell RNA sequencing revealed activation of the interferon response on TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes., Conclusion: Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumour immunity by inducing interferon signalling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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26. Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy.
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Dammeijer F, van Gulijk M, Klaase L, van Nimwegen M, Bouzid R, Hoogenboom R, Joosse ME, Hendriks RW, van Hall T, and Aerts JG
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- Animals, Mice, Phosphorylation, Receptors, Interleukin-2 metabolism, STAT5 Transcription Factor metabolism, Immunotherapy, Janus Kinase 3 antagonists & inhibitors, Neoplasms therapy, T-Lymphocytes immunology
- Abstract
Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)-STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i administration inhibited antitumor T-cell effector function, low-dose chronic JAK3i significantly improved T-cell responses and decreased tumor load in mouse models of solid cancer. Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared with both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy., (©2022 American Association for Cancer Research.)
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- 2022
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27. Regulatory T Cell Depletion Using a CRISPR Fc-Optimized CD25 Antibody.
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van Elsas MJ, van der Schoot JMS, Bartels A, Steuten K, van Dalen D, Wijfjes Z, Figdor CG, van Hall T, van der Burg SH, Verdoes M, and Scheeren FA
- Subjects
- Animals, Clustered Regularly Interspaced Short Palindromic Repeats, Immunoglobulin Fc Fragments metabolism, Immunoglobulin G metabolism, Interleukin-2 Receptor alpha Subunit metabolism, Lymphocyte Depletion methods, Mice, Rats, Neoplasms metabolism, T-Lymphocytes, Regulatory
- Abstract
Regulatory T cells (T
regs ) are major drivers behind immunosuppressive mechanisms and present a major hurdle for cancer therapy. Tregs are characterized by a high expression of CD25, which is a potentially valuable target for Treg depletion to alleviate immune suppression. The preclinical anti-CD25 (αCD25) antibody, clone PC-61, has met with modest anti-tumor activity due to its capacity to clear Tregs from the circulation and lymph nodes, but not those that reside in the tumor. The optimization of the Fc domain of this antibody clone has been shown to enhance the intratumoral Treg depletion capacity. Here, we generated a stable cell line that produced optimized recombinant Treg -depleting antibodies. A genome engineering strategy in which CRISPR-Cas9 was combined with homology-directed repair (CRISPR-HDR) was utilized to optimize the Fc domain of the hybridoma PC-61 for effector functions by switching it from its original rat IgG1 to a mouse IgG2a isotype. In a syngeneic tumor mouse model, the resulting αCD25-m2a (mouse IgG2a isotype) antibody mediated the effective depletion of tumor-resident Tregs , leading to a high effector T cell (Teff ) to Treg ratio. Moreover, a combination of αCD25-m2a and an αPD-L1 treatment augmented tumor eradication in mice, demonstrating the potential for αCD25 as a cancer immunotherapy.- Published
- 2022
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28. Preinduced reovirus-specific T-cell immunity enhances the anticancer efficacy of reovirus therapy.
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Groeneveldt C, Kinderman P, van Stigt Thans JJC, Labrie C, Griffioen L, Sluijter M, van den Wollenberg DJM, Hoeben RC, den Haan JMM, van der Burg SH, van Hall T, and van Montfoort N
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Immunotherapy, Mice, Tumor Microenvironment, Neoplasms, Oncolytic Virotherapy methods, Oncolytic Viruses
- Abstract
Background: Many solid tumors do not respond to immunotherapy due to their immunologically cold tumor microenvironment (TME). We and others found that oncolytic viruses (OVs), including reovirus type 3 Dearing, can enhance the efficacy of immunotherapy by recruiting CD8
+ T cells to the TME. A significant part of the incoming CD8+ T cells is directed toward reovirus itself, which may be detrimental to the efficacy of OVs. However, here we aim to exploit these incoming virus-specific T cells as anticancer effector cells., Methods: We performed an in-depth characterization of the reovirus-induced T-cell response in immune-competent mice bearing pancreatic KPC3 tumors. The immunodominant CD8+ T-cell epitope of reovirus was identified using epitope prediction algorithms and peptide arrays, and the quantity and quality of reovirus-specific T cells after reovirus administration were assessed using high-dimensional flow cytometry. A synthetic long peptide (SLP)-based vaccination strategy was designed to enhance the intratumoral frequency of reovirus-specific CD8+ T cells., Results: Reovirus administration did not induce tumor-specific T cells but rather induced high frequencies of reovirus-specific CD8+ T cells directed to the immunodominant epitope. Priming of reovirus-specific T cells required a low-frequent population of cross-presenting dendritic cells which was absent in Batf3-/- mice. While intratumoral and intravenous reovirus administration induced equal systemic frequencies of reovirus-specific T cells, reovirus-specific T cells were highly enriched in the TME exclusively after intratumoral administration. Here, they displayed characteristics of potent effector cells with high expression of KLRG1, suggesting they may be responsive against local reovirus-infected cells. To exploit these reovirus-specific T cells as anticancer effector cells, we designed an SLP-based vaccination strategy to induce a strong T-cell response before virotherapy. These high frequencies of circulating reovirus-specific T cells were reactivated on intratumoral reovirus administration and significantly delayed tumor growth., Conclusions: These findings provide proof of concept that OV-specific T cells, despite not being tumor-specific, can be exploited as potent effector cells for anticancer treatment when primed before virotherapy. This is an attractive strategy for low-immunogenic tumors lacking tumor-specific T cells., Competing Interests: Competing interests: CG, NvM, and TvH filed a patent (P335646NL) regarding the research described in this manuscript. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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29. A Single-Domain TCR-like Antibody Selective for the Qa-1 b /Qdm Peptide Complex Enhances Tumoricidal Activity of NK Cells via Blocking the NKG2A Immune Checkpoint.
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Ghaffari S, Upchurch-Ange K, Gimlin S, Tripathi T, Sluijter M, Middelburg J, van Hall T, and Weidanz J
- Subjects
- Animals, Antibodies metabolism, Mice, NK Cell Lectin-Like Receptor Subfamily C metabolism, Peptides, Receptors, Antigen, T-Cell metabolism, Histocompatibility Antigens Class I, Killer Cells, Natural
- Abstract
The NKG2A/HLA-E axis is an immune checkpoint that suppresses immune effector activity in the tumor microenvironment. In mice, the ligand for the NKG2A/CD94 inhibitory receptor is the nonclassical MHC molecule Qa-1
b , the HLA-E ortholog, which presents the peptide AMAPRTLLL, referred to as Qdm (for Qa-1 determinant modifier). This dominant peptide is derived from the leader sequences of murine classical MHC class I encoded by the H-2D and -L loci. To broaden our understanding of Qa-1b /Qdm peptide complex biology and its tumor protective role, we identified a TCR-like Ab from a single domain VHH library using yeast surface display. The TCR-like Ab (EXX-1) binds only to the Qa-1b /Qdm peptide complex and not to Qa-1b alone or Qa-1b loaded with control peptides. Conversely, currently available Abs to Qa-1b bind independent of peptide loaded. Flow cytometric results revealed that EXX-1 selectively bound to Qa-1b /Qdm-positive B16F10, RMA, and TC-1 mouse tumor cells but only after pretreatment with IFN-γ; no binding was observed following genetic knockdown of Qa-1b or Qdm peptide. Furthermore, EXX-1 Ab blockade promoted NK cell-mediated tumor cell lysis in vitro. Our findings show that EXX-1 has exquisite binding specificity for the Qa-1b /Qdm peptide complex, making it a valuable research tool for further investigation of the Qa-1b /Qdm peptide complex expression and regulation in healthy and diseased cells and for evaluation as an immune checkpoint blocking Ab in syngeneic mouse tumor models., (Copyright © 2022 by The American Association of Immunologists, Inc.)- Published
- 2022
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30. Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease cathepsin S.
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Harryvan TJ, Visser M, de Bruin L, Plug L, Griffioen L, Mulder A, van Veelen PA, van der Heden van Noort GJ, Jongsma ML, Meeuwsen MH, Wiertz EJ, Santegoets SJ, Hardwick JC, Van Hall T, Neefjes J, Van der Burg SH, Hawinkels LJ, and Verdegaal EM
- Subjects
- Animals, Cathepsins, Cross-Priming, Humans, Lysosomes metabolism, Mice, Peptide Hydrolases genetics, Peptide Hydrolases metabolism, Up-Regulation, Cancer-Associated Fibroblasts metabolism, Colorectal Neoplasms genetics
- Abstract
Background: Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. Whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function is unknown., Methods: In this study, we investigated the ability of human colorectal cancer (CRC)-derived CAFs to cross-present neoantigen-derived synthetic long peptides (SLPs), corresponding to tumor-derived mutant peptides, and how this affects tumor-specific T-cell function. Processing of the SLP was studied by targeting components of the cross-presentation machinery through CRISPR/Cas9 and siRNA-mediated genetic ablation to identify the key molecules involved in fibroblast-mediated cross-presentation. Multispectral flow cytometry and killing assays were performed to study the effect of fibroblast cross-presentation on T cell function., Results: Here, we show that human CRC-derived CAFs display an enhanced capacity to cross-present neoantigen-derived SLPs when compared with normal colonic fibroblasts. Cross-presentation of antigens by fibroblasts involved the lysosomal protease cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD137) and increased exhaustion (TIM3, LAG3 and CD39) marker expression., Conclusion: These data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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31. NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division.
- Author
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Borst L, Sluijter M, Sturm G, Charoentong P, Santegoets SJ, van Gulijk M, van Elsas MJ, Groeneveldt C, van Montfoort N, Finotello F, Trajanoski Z, Kiełbasa SM, van der Burg SH, and van Hall T
- Subjects
- Animals, Antigens, CD physiology, CD8-Positive T-Lymphocytes immunology, Cell Division, Hepatitis A Virus Cellular Receptor 2 physiology, Humans, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell physiology, Receptors, Immunologic physiology, Transforming Growth Factor beta pharmacology, Tumor Microenvironment, Lymphocyte Activation Gene 3 Protein, Immune Checkpoint Proteins physiology, NK Cell Lectin-Like Receptor Subfamily C physiology
- Abstract
The surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in several efficacy trials for different tumor indications, it is important to characterize the NKG2A
+ CD8 T cell population in the context of other inhibitory receptors. Here we used a well-controlled culture system to study the kinetics of inhibitory receptor expression. Naïve mouse CD8 T cells were synchronously and repeatedly activated by artificial antigen presenting cells in the presence of the homeostatic cytokine IL-7. The results revealed NKG2A as a late inhibitory receptor, expressed after repeated cognate antigen stimulations. In contrast, the expression of PD-1, TIGIT and LAG-3 was rapidly induced, hours after first contact and subsequently down regulated during each resting phase. This late, but stable expression kinetics of NKG2A was most similar to that of TIM-3 and CD39. Importantly, single-cell transcriptomics of human tumor-infiltrating lymphocytes (TILs) showed indeed that these receptors were often coexpressed by the same CD8 T cell cluster. Furthermore, NKG2A expression was associated with cell division and was promoted by TGF-β in vitro, although TGF-β signaling was not necessary in a mouse tumor model in vivo. In summary, our data show that PD-1 reflects recent TCR triggering, but that NKG2A is induced after repeated antigen stimulations and represents a late inhibitory receptor. Together with TIM-3 and CD39, NKG2A might thus mark actively dividing tumor-specific TILs., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)- Published
- 2022
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32. Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement.
- Author
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Marijt KA, Griffioen L, Blijleven L, van der Burg SH, and van Hall T
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2 genetics, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung metabolism, Adenocarcinoma of Lung pathology, Antigen Presentation immunology, Antigens, Neoplasm, Dendritic Cells immunology, Epitopes, T-Lymphocyte immunology, HLA-A2 Antigen immunology, Humans, LDL-Receptor Related Protein-Associated Protein metabolism, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, Protein Sorting Signals, Tumor Cells, Cultured, Tumor Escape, ATP Binding Cassette Transporter, Subfamily B, Member 2 metabolism, Adenocarcinoma of Lung immunology, CD8-Positive T-Lymphocytes immunology, Cross-Priming, Lung Neoplasms immunology, Peptide Fragments pharmacology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Cancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their 'self' origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP1
21-30 -specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121-30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121-30 -specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials., (© 2021. The Author(s).)- Published
- 2022
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33. Association of cognitive function with increased risk of cancer death and all-cause mortality: Longitudinal analysis, systematic review, and meta-analysis of prospective observational studies.
- Author
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Rostamian S, le Cessie S, Marijt KA, Jukema JW, Mooijaart SP, van Buchem MA, van Hall T, Gussekloo J, and Trompet S
- Subjects
- Aged, Aged, 80 and over, Cardiovascular Diseases drug therapy, Cognitive Dysfunction drug therapy, Female, Humans, Male, Neoplasms drug therapy, Pravastatin therapeutic use, Prospective Studies, Cardiovascular Diseases mortality, Cognition, Cognitive Dysfunction mortality, Neoplasms mortality
- Abstract
Background: Disturbed cognitive function is associated with several causes of mortality; however, the association between cognitive function and the risk of cancer death has not been extensively investigated yet. We aimed to evaluate the association of cognitive function with the risk of cancer death and all-cause mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) and Leiden 85-plus Study. Additionally, a systematic review and meta-analysis of longitudinal studies were conducted to evaluate the association of cognitive function and risk of cancer death., Methods: Risk of cancer death and all-cause mortality were reported using hazard ratios (HRs) with 95% confidence interval (CI) in tertiles of cognitive function of PROSPER and Leiden85-Plus Study. Additionally, PubMed, Embase, Web of Science, Cochrane, PsycINFO, Academic Search Premier, CINHAL, and Emcare were searched up to November 1st, 2020 to perform a systematic review and meta-analysis. The relative risks (RRs) with 95%CI of cancer death per each standard deviation lower performance in cognitive measurements were calculated., Results: Participants of PROSPER had 1.65-fold (95%CI 1.11-2.47) greater risk of cancer death (P for trend = 0.016) and 1.85-fold (95%CI 1.46-2.34) higher risk of all-cause mortality (P for trend<0.001), in multivariable models. Results of the Leiden-85 Plus Study showed that subjects with MMSE score below 24 had a lower chance of cancer death (HR 0.79, 95%CI 0.36-1.70, P for trend = 0.820) but had 2.18-fold (95%CI 1.57-3.02) higher risk of all-cause mortality compared to the reference group (P for trend<0.001). Besides, the results of systematic review and meta-analysis showed that per each standard deviation lower performance in cognitive function, individuals were at a 10% higher chance of cancer death (RR 1.10, 95%CI 1.00-1.20, P-value = 0.044)., Conclusions: Lower cognitive function performance is associated with a marginally increased risk of cancer death, in line with a significantly greater risk of all-cause mortality., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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34. Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome.
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Najidh S, Tensen CP, van der Sluijs-Gelling AJ, Teodosio C, Cats D, Mei H, Kuipers TB, Out-Luijting JJ, Zoutman WH, van Hall T, Orfao A, Almeida J, van Dongen JJM, and Vermeer MH
- Subjects
- Aged, Aged, 80 and over, Antigens, CD analysis, Female, Flow Cytometry, Humans, Immunophenotyping, Lymphocytes pathology, Male, Middle Aged, Prospective Studies, Sezary Syndrome pathology, Skin Neoplasms pathology, Sezary Syndrome diagnosis, Skin Neoplasms diagnosis
- Abstract
Sézary syndrome (SS) is an aggressive leukemic form of cutaneous T-cell lymphoma with neoplastic CD4+ T cells present in skin, lymph nodes, and blood. Despite advances in therapy, prognosis remains poor, with a 5-year overall survival of 30%. The immunophenotype of Sézary cells is diverse, which hampers efficient diagnosis, sensitive disease monitoring, and accurate assessment of treatment response. Comprehensive immunophenotypic profiling of Sézary cells with an in-depth analysis of maturation and functional subsets has not been performed thus far. We immunophenotypically profiled 24 patients with SS using standardized and sensitive EuroFlow-based multiparameter flow cytometry. We accurately identified and quantified Sézary cells in blood and performed an in-depth assessment of their phenotypic characteristics in comparison with their normal counterparts in the blood CD4+ T-cell compartment. We observed inter- and intrapatient heterogeneity and phenotypic changes over time. Sézary cells exhibited phenotypes corresponding with classical and nonclassical T helper subsets with different maturation phenotypes. We combined multiparameter flow cytometry analyses with fluorescence-activated cell sorting and performed RNA sequencing studies on purified subsets of malignant Sézary cells and normal CD4+ T cells of the same patients. We confirmed pure monoclonality in Sézary subsets, compared transcriptomes of phenotypically distinct Sézary subsets, and identified novel downregulated genes, most remarkably THEMIS and LAIR1, which discriminate Sézary cells from normal residual CD4+ T cells. Together, these findings further unravel the heterogeneity of Sézary cell subpopulations within and between patients. These new data will support improved blood staging and more accurate disease monitoring., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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35. Immune Checkpoint Therapy: Tumor Draining Lymph Nodes in the Spotlights.
- Author
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Fransen MF, van Hall T, and Ossendorp F
- Subjects
- Animals, Humans, Neoadjuvant Therapy, Neoplasms pathology, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy methods, Lymphocytes, Tumor-Infiltrating immunology, Neoplasms drug therapy, Neoplasms immunology, Sentinel Lymph Node immunology
- Abstract
Tumor-draining lymph nodes play a paradoxical role in cancer. Surgeons often resect these sentinel lymph nodes to determine metastatic spread, thereby enabling prognosis and treatment. However, lymph nodes are vital organs for the orchestration of immune responses, due to the close encounters of dedicated immune cells. In view of the success of immunotherapy, the removal of tumor-draining lymph nodes needs to be re-evaluated and viewed in a different light. Recently, an important role for tumor-draining lymph nodes has been proposed in the immunotherapy of cancer. This new insight can change the use of immune checkpoint therapy, particularly with respect to the use in neoadjuvant settings in which lymph nodes are still operational.
- Published
- 2021
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36. IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors.
- Author
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Beyranvand Nejad E, Labrie C, van Elsas MJ, Kleinovink JW, Mittrücker HW, Franken KLMC, Heink S, Korn T, Arens R, van Hall T, and van der Burg SH
- Subjects
- Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cancer Vaccines immunology, Cell Line, Tumor, Cytotoxicity, Immunologic drug effects, Female, Injections, Subcutaneous, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Inbred C57BL, Mice, Knockout, Neoplasms immunology, Neoplasms metabolism, Oligodeoxyribonucleotides immunology, Papillomavirus E7 Proteins immunology, Phenotype, Receptors, Interleukin-6 genetics, Receptors, Interleukin-6 metabolism, Signal Transduction, Tumor Burden drug effects, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism, Mice, Cancer Vaccines administration & dosage, Interleukin-6 metabolism, Neoplasms drug therapy, Oligodeoxyribonucleotides administration & dosage, Papillomavirus E7 Proteins administration & dosage, Tumor-Associated Macrophages drug effects
- Abstract
Background: High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective., Methods: IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1., Control: Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6ra
fl/fl ×LysMcre+ mice., Results: Our therapeutic vaccination protocol elicits a strong tumor-specific CD8+ T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8+ T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6rafl/fl ×LysMcre+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages.+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages., Conclusion: IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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37. Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors.
- Author
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Middelburg J, Kemper K, Engelberts P, Labrijn AF, Schuurman J, and van Hall T
- Abstract
Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of the CD3-bispecific antibody therapy field and identify intrinsic hurdles in solid cancers. Furthermore, we describe potential combinatorial approaches to overcome these challenges in order to generate selective and more effective responses.
- Published
- 2021
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38. Interleukin-6-mediated resistance to immunotherapy is linked to impaired myeloid cell function.
- Author
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Beyranvand Nejad E, Labrie C, van der Sluis TC, van Duikeren S, Franken KLMC, Roosenhoff R, Arens R, van Hall T, and van der Burg SH
- Subjects
- Animals, Cancer Vaccines immunology, Cell Line, Tumor transplantation, Cisplatin pharmacology, Cisplatin therapeutic use, Disease Models, Animal, Drug Resistance, Neoplasm immunology, Female, Histocompatibility Antigens Class II metabolism, Human papillomavirus 16 immunology, Humans, Immunotherapy methods, Interleukin-6 genetics, Mice, Myeloid Cells metabolism, Neoplasms immunology, Neoplasms pathology, Neoplasms virology, Papillomavirus Infections immunology, Papillomavirus Infections pathology, Papillomavirus Infections virology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Vaccines, Subunit immunology, Cancer Vaccines administration & dosage, Interleukin-6 metabolism, Myeloid Cells immunology, Neoplasms therapy, Papillomavirus Infections therapy
- Abstract
High serum levels of interleukin-6 (IL-6) correlate with poor prognosis and chemotherapy resistance in several cancers. The underlying mechanisms and its effects on immunotherapy are largely unknown. To address this, we developed a human papillomavirus type 16 (HPV16)-associated tumor model expressing IL-6 to investigate the impact of tumor-expressed IL-6 during cisplatin chemotherapy and HPV16 synthetic long peptide vaccination as immunotherapy. The effects of tumor-produced IL-6 on tumor growth, survival and the tumor microenvironment were analyzed. Our data demonstrated that tumor-produced IL-6 conferred resistance to cisplatin and therapeutic vaccination. This was not caused by a changed in vitro or in vivo growth rate of tumor cells, or a changed sensitivity of tumor cells to chemotherapy or T-cell-mediated killing. Furthermore, no overt differences in the frequencies of tumor-infiltrating subsets of T cells or CD11b
+ myeloid cells were observed. IL-6, however, affected the systemic and local function of myeloid cells, reflected by a strong reduction of major histocompatibility complex (MHC) class II expression on all major myeloid cell subtypes. Resistance to both therapies was associated with a changed intratumoral influx of MHC class II+ myeloid cells toward myeloid cells with no or lower MHC class II expression. Importantly, while these IL-6-mediated effects provided resistance to the immunotherapy and chemotherapy as single therapies, their combination still successfully mediated tumor control. In conclusion, IL-6-mediated therapy resistance is caused by an extrinsic mechanism involving an impaired function of intratumoral myeloid cells. The fact that resistance can be overcome by combination therapies provides direction to more effective therapies for cancer., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)- Published
- 2021
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39. The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes.
- Author
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Dammeijer F, van Gulijk M, Mulder EE, Lukkes M, Klaase L, van den Bosch T, van Nimwegen M, Lau SP, Latupeirissa K, Schetters S, van Kooyk Y, Boon L, Moyaart A, Mueller YM, Katsikis PD, Eggermont AM, Vroman H, Stadhouders R, Hendriks RW, Thüsen JV, Grünhagen DJ, Verhoef C, van Hall T, and Aerts JG
- Subjects
- Adult, Animals, B7-H1 Antigen antagonists & inhibitors, Cell Line, Tumor, Dendritic Cells immunology, Female, Humans, Immune Checkpoint Inhibitors therapeutic use, Lymph Nodes drug effects, Male, Melanoma immunology, Melanoma pathology, Mice, Middle Aged, Neoplasm Staging, T-Lymphocytes drug effects, Tumor Microenvironment drug effects, Xenograft Model Antitumor Assays, B7-H1 Antigen metabolism, Immune Checkpoint Inhibitors pharmacology, Lymph Nodes immunology, Melanoma drug therapy, Programmed Cell Death 1 Receptor metabolism, T-Lymphocytes immunology
- Abstract
PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1
+ T cells which closely associate with PD-L1+ cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control. Moreover, we show that abundant PD-1/PD-L1-interactions in TDLNs of nonmetastatic melanoma patients, but not those in corresponding tumors, associate with early distant disease recurrence. These findings point at a critical role for PD-L1 expression in TDLNs in governing systemic anti-tumor immunity, identifying high-risk patient groups amendable to adjuvant PD-1/PD-L1-blockade therapy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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40. The NKG2A-HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment.
- Author
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Borst L, van der Burg SH, and van Hall T
- Subjects
- B7-H1 Antigen genetics, B7-H1 Antigen immunology, Cancer Vaccines immunology, Cancer Vaccines therapeutic use, Histocompatibility Antigens Class I immunology, Humans, Immune Checkpoint Inhibitors therapeutic use, Killer Cells, Natural immunology, NK Cell Lectin-Like Receptor Subfamily C immunology, Neoplasms genetics, Neoplasms immunology, Neoplasms pathology, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Tumor Microenvironment immunology, HLA-E Antigens, Histocompatibility Antigens Class I genetics, NK Cell Lectin-Like Receptor Subfamily C genetics, Neoplasms drug therapy, Tumor Microenvironment drug effects
- Abstract
The success of checkpoint blockade therapy revolutionized cancer treatment. However, we need to increase the fraction of responding patients and overcome acquired resistance to these therapies. Recently, the inhibitory receptor NKG2A received attention as a new kid on the block of immune checkpoints. This receptor is selectively expressed on cytotoxic lymphocytes, including natural killer cells and CD8 T cells, and NKG2A
+ T cells are preferentially residing in tissues, like the tumor microenvironment. Its ligand, histocompatibility leucocyte antigen E (HLA-E), is a conserved nonclassical HLA class I molecule that binds a limited peptide repertoire and its expression is commonly detected in human cancer. NKG2A blockade as a standalone therapy appears poorly effective in mouse tumor models, however, in the presence of activated T cells, for example, induced by PD-1/PD-L1 blockade or cancer vaccines, exerts strongly enhanced efficacy. Clinical trials demonstrated safety of the humanized NKG2A-blocking antibody, monalizumab, and first results of phase II trials demonstrate encouraging durable response rates. Further development of this axis is clearly warranted., (©2020 American Association for Cancer Research.)- Published
- 2020
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41. Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy.
- Author
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Groeneveldt C, Kinderman P, van den Wollenberg DJM, van den Oever RL, Middelburg J, Mustafa DAM, Hoeben RC, van der Burg SH, van Hall T, and van Montfoort N
- Subjects
- Animals, Antibodies, Bispecific pharmacology, Female, Humans, Male, Mice, Tumor Microenvironment, Antibodies, Bispecific therapeutic use, Immunotherapy methods, Oncolytic Virotherapy methods
- Abstract
Background: T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors., Methods: The mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy. Immune-competent KPC3 tumor-bearing mice were intratumorally injected with reovirus type 3 Dearing strain and the reovirus-induced changes in the tumor microenvironment and spleen were analyzed over time by NanoString analysis, quantitative RT-PCR and multicolor flow cytometry. The efficacy of reovirus in combination with systemically injected CD3-bsAbs was evaluated in immune-competent mice with established KPC3 or B16.F10 tumors, and in the close-to-patient human epidermal growth factor receptor 2 (HER2)
+ breast cancer model BT474 engrafted in immunocompromised mice with human T cells as effector cells., Results: Replication-competent reovirus induced an early interferon signature, followed by a strong influx of natural killer cells and CD8+ T cells, at the cost of FoxP3+ Tregs. Viral replication declined after 7 days and was associated with a systemic activation of lymphocytes and the emergence of intratumoral reovirus-specific CD8+ T cells. Although tumor-infiltrating T cells were mostly reovirus-specific and not tumor-specific, they served as non-exhausted effector cells for the subsequently systemically administered CD3-bsAbs. Combination treatment of reovirus and CD3-bsAbs led to the regression of large, established KPC3, B16.F10 and BT474 tumors. Reovirus as a preconditioning regimen performed significantly better than simultaneous or early administration of CD3-bsAbs. This combination treatment induced regressions of distant lesions that were not injected with reovirus, and systemic administration of both reovirus and CD3-bsAbs also led to tumor control. This suggests that this therapy might also be effective for metastatic disease., Conclusions: Oncolytic reovirus administration represents an effective strategy to induce a local interferon response and strong T-cell influx, thereby sensitizing the tumor microenvironment for subsequent CD3-bsAb therapy. This combination therapy warrants further investigation in patients with non-inflamed solid tumors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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42. Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy.
- Author
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Beyranvand Nejad E, Labrie C, Abdulrahman Z, van Elsas MJ, Rademaker E, Kleinovink JW, van der Sluis TC, van Duikeren S, Teunisse AFAS, Jochemsen AG, Oosting J, de Miranda NFCC, Van Hall T, Arens R, and van der Burg SH
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Drug Resistance, Neoplasm immunology, Immunotherapy methods, Myeloid Cells immunology
- Abstract
Background: Immunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments., Methods: We exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients., Results: Full tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-α and transforming growth factor-β signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in naïve hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8
+ T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients., Conclusion: An immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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43. Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models.
- Author
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van Elsas M, Kleinovink JW, Moerland M, Feiss G, Beyrend G, Arens R, Mei H, Nibbering PH, Jirka SM, van Hall T, and van der Burg SH
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Mice, Tumor Microenvironment, Neutrophils metabolism
- Abstract
Background: Neutrophils have been reported to have protumor, antitumor or neutral effects in cancer progression. The underlying causes for this functional variability are not clear., Methods: We studied the role of neutrophils in six different mouse tumor models by intratumoral injection of antimicrobial peptides or vaccination. Changes in systemic and intratumoral immune cells were analyzed by flow-cytometry and mass-cytometry. The role of neutrophils was studied by antibody-mediated neutrophil depletion. Neutrophils from different mouse strains were compared by RNA sequencing., Results: The antimicrobial peptide Omiganan reduced the growth of TC-1 tumors in BL/6 mice and CT26 tumors in BALB/c mice. No significant effects were observed in B16F10, MC38 and 4T1 tumors. Growth delay was associated with increased abundance of neutrophils in TC-1 but not CT26 tumors. Systemic neutrophil depletion abrogated Omiganan efficacy in TC-1 but further reduced growth of CT26, indicating that neutrophils were required for the antitumor effect in TC-1 but suppressed tumor control in CT26. Neutrophils were also required for a therapeutic vaccine-induced T-cell mediated control of RMA tumors in BL/6 mice. Clearly, the circulating and intratumoral neutrophils differed in the expression of Ly6G and CD62L, between TC-1 and CT26 and between blood neutrophils of tumor-naïve BL/6 and BALB/c mice. RNA-sequencing revealed that neutrophils from BL/6 mice but not BALB/c mice displayed a robust profile of immune activation, matching their opposing roles in TC-1 and RMA versus CT26., Conclusions: Neutrophil functionality differs strongly between mouse strains and tumor types, with consequences for tumor progression and therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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44. Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model.
- Author
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Lau SP, van Montfoort N, Kinderman P, Lukkes M, Klaase L, van Nimwegen M, van Gulijk M, Dumas J, Mustafa DAM, Lievense SLA, Groeneveldt C, Stadhouders R, Li Y, Stubbs A, Marijt KA, Vroman H, van der Burg SH, Aerts J, van Hall T, Dammeijer F, and van Eijck CHJ
- Subjects
- Adenocarcinoma pathology, Animals, Cancer Vaccines pharmacology, Carcinoma, Pancreatic Ductal pathology, Disease Models, Animal, Female, Humans, Mice, Adenocarcinoma therapy, Cancer Vaccines therapeutic use, Carcinoma, Pancreatic Ductal therapy, Dendritic Cells metabolism
- Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to treatment including checkpoint-blockade immunotherapy. We hypothesized that a bimodal treatment approach consisting of dendritic cell (DC) vaccination to prime tumor-specific T cells, and a strategy to reprogram the desmoplastic tumor microenvironment (TME) would be needed to break tolerance to these pancreatic cancers. As a proof-of-concept, we investigated the efficacy of combined DC vaccination with CD40-agonistic antibodies in a poorly immunogenic murine model of PDAC. Based on the rationale that mesothelioma and pancreatic cancer share a number of tumor associated antigens, the DCs were loaded with either pancreatic or mesothelioma tumor lysates., Methods: Immune-competent mice with subcutaneously or orthotopically growing KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) PDAC tumors were vaccinated with syngeneic bone marrow-derived DCs loaded with either pancreatic cancer (KPC) or mesothelioma (AE17) lysate and consequently treated with FGK45 (CD40 agonist). Tumor progression was monitored and immune responses in TME and lymphoid organs were analyzed using multicolor flow cytometry and NanoString analyzes., Results: Mesothelioma-lysate loaded DCs generated cross-reactive tumor-antigen-specific T-cell responses to pancreatic cancer and induced delayed tumor outgrowth when provided as prophylactic vaccine. In established disease, combination with stimulating CD40 antibody was necessary to improve survival, while anti-CD40 alone was ineffective. Extensive analysis of the TME showed that anti-CD40 monotherapy did improve CD8 +T cell infiltration, but these essential effector cells displayed hallmarks of exhaustion, including PD-1, TIM-3 and NKG2A. Combination therapy induced a strong change in tumor transcriptome and mitigated the expression of inhibitory markers on CD8 +T cells., Conclusion: These results demonstrate the potency of DC therapy in combination with CD40-stimulation for the treatment of pancreatic cancer and provide directions for near future clinical trials., Competing Interests: Competing interests: JA: Stock or other Ownership: Amphera. Consulting or Advisory Role: Eli-Lilly, MSD Oncology, Bristol-Myers Squibb, Roche Speakers Bureau: AstraZeneca, Takeda, Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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45. Vaccination against Nonmutated Neoantigens Induced in Recurrent and Future Tumors.
- Author
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Garrido G, Schrand B, Levay A, Rabasa A, Ferrantella A, Da Silva DM, D'Eramo F, Marijt KA, Zhang Z, Kwon D, Kortylewski M, Kast WM, Dudeja V, van Hall T, and Gilboa E
- Subjects
- ATP-Binding Cassette Transporters antagonists & inhibitors, ATP-Binding Cassette Transporters immunology, Animals, Antigen Presentation immunology, Cancer Vaccines immunology, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Recurrence, Local immunology, Neoplasms immunology, RNA, Small Interfering genetics, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines administration & dosage, Neoplasm Recurrence, Local therapy, Neoplasms therapy
- Abstract
Vaccination of patients against neoantigens expressed in concurrent tumors, recurrent tumors, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Human CD8
+ T cells stimulated with TAPlow dendritic cells elicited a polyclonal T-cell response that recognized tumor cells with experimentally reduced TAP expression. Vaccination against TAP downregulation-induced antigens overcomes the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a simpler vaccination strategy that will be applicable to most patients with cancer., (©2020 American Association for Cancer Research.)- Published
- 2020
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46. To TAP or not to TAP: alternative peptides for immunotherapy of cancer.
- Author
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Marijt KA and van Hall T
- Subjects
- Antigen Presentation, Antigens, Humans, Immunotherapy, Peptides, Histocompatibility Antigens Class I, Neoplasms therapy
- Abstract
Intracellular processing of antigens is crucial for the generation of T cell immunity towards cancers, since cleaved protein products are the molecular targets of these adaptive lymphocytes. The majority of antigenic peptides requires the TAP transporter to gain access to the peptide loading complex in the ER lumen where they bind MHC class I (MHC-I). This pivotal role of TAP in antigen processing makes the system vulnerable for modifications in cancer cells and indeed human cancers frequently silence this gene epigenetically. Interestingly, TAP-independent processing pathways then become apparent and partly restore MHC class I presentation with alternative peptides. In this review we discuss recent insights on how TAP-independent processing of immunogenic peptides occurs, and how these antigens can be exploited for cancer immunotherapy., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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47. Immunotherapeutic Potential of TGF-β Inhibition and Oncolytic Viruses.
- Author
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Groeneveldt C, van Hall T, van der Burg SH, Ten Dijke P, and van Montfoort N
- Subjects
- Humans, Immunotherapy trends, Neoplasms therapy, Oncolytic Virotherapy trends, Oncolytic Viruses immunology, Transforming Growth Factor beta antagonists & inhibitors, Transforming Growth Factor beta immunology
- Abstract
In cancer immunotherapy, a patient's own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-β (TGF-β)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-β signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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48. Future Challenges in Cancer Resistance to Immunotherapy.
- Author
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van Elsas MJ, van Hall T, and van der Burg SH
- Abstract
Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.
- Published
- 2020
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49. Immunogenicity of rat-neu + mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment.
- Author
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Sow HS, Benonisson H, Brouwers C, Linssen MM, Camps M, Breukel C, Claassens J, van Hall T, Ossendorp F, Fransen MF, and Verbeek JS
- Subjects
- Animals, Antibodies, Monoclonal, Humanized therapeutic use, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Cell Line, Tumor, Female, Flow Cytometry, Lapatinib therapeutic use, Leukocyte Common Antigens metabolism, Male, Mice, Mice, Inbred BALB C, Quinolines therapeutic use, Rats, Receptor, ErbB-2 genetics, Signal Transduction, T-Lymphocytes drug effects, T-Lymphocytes immunology, Trastuzumab therapeutic use, Antibodies, Monoclonal therapeutic use, Mammary Neoplasms, Animal drug therapy, Mammary Neoplasms, Animal immunology, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental immunology, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, T-Lymphocytes metabolism
- Abstract
The use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2
+ breast cancer patients. The tumour mutational burden and the presence of tumour infiltrating lymphocytes (TILs) clearly correlate with response to trastuzumab. Here, we investigated if the immunogenicity of the transplantable rat-neu+ tumour cell line (TUBO) derived from a BALB/c-NeuT primary tumour is associated with the response to anti-neu mAb therapy. We compared the TUBO tumour outgrowth and tumour infiltrating T cells in isogenic (BALB/c-NeuT) and non-isogenic (WT BALB/c) recipient mice. Furthermore, therapeutic efficacy of anti-neu mAb and the contribution of T cells were examined in both mouse strains. The outgrowth of untreated tumours was significantly better in BALB/c-NeuT than WT BALB/c mice. Moreover, tumour infiltrating T cells were more abundantly present in WT BALB/c than BALB/c-NeuT mice, showing that the TUBO tumour was more immunogenic in WT BALB/c mice. In TUBO tumour bearing WT BALB/c mice, anti-neu mAb therapy resulted in an increase of tumour infiltrating T cells and long-term survival. When T cells were depleted, this strong anti-tumour effect was reduced to an outgrowth delay. In contrast, in TUBO tumour bearing BALB/c-NeuT mice, treatment with anti-neu mAb resulted only in tumour outgrowth delay, both in the presence and absence of T cells. We concluded that in immunogenic tumours the response to anti-neu mAb therapy is enhanced by additional T cell involvement compared to the response to anti-neu mAb in non-immunogenic tumours.- Published
- 2020
- Full Text
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50. Monalizumab: inhibiting the novel immune checkpoint NKG2A.
- Author
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van Hall T, André P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, and Vivier E
- Subjects
- Animals, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Disease Models, Animal, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class I metabolism, Humans, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Mice, NK Cell Lectin-Like Receptor Subfamily C immunology, NK Cell Lectin-Like Receptor Subfamily C metabolism, Neoplasms immunology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, HLA-E Antigens, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents, Immunological pharmacology, NK Cell Lectin-Like Receptor Subfamily C antagonists & inhibitors, Neoplasms drug therapy
- Abstract
The implementation of immune checkpoint inhibitors to the oncology clinic signified a new era in cancer treatment. After the first indication of melanoma, an increasing list of additional cancer types are now treated with immune system targeting antibodies to PD-1, PD-L1 and CTLA-4, alleviating inhibition signals on T cells. Recently, we published proof-of-concept results on a novel checkpoint inhibitor, NKG2A. This receptor is expressed on cytotoxic lymphocytes, including NK cells and subsets of activated CD8
+ T cells. Blocking antibodies to NKG2A unleashed the reactivity of these effector cells resulting in tumor control in multiple mouse models and an early clinical trial. Monalizumab is inhibiting this checkpoint in human beings and future clinical trials will have to reveal its potency in combination with other cancer treatment options.- Published
- 2019
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