32 results on '"Rebekka Duhen"'
Search Results
2. Tumor resident memory CD8 T cells and concomitant tumor immunity develop independently of CD4 help
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Terry R. Medler, Gwen Kramer, Shelly Bambina, Andrew J. Gunderson, Alejandro Alice, Tiffany Blair, Lauren Zebertavage, Thomas Duhen, Rebekka Duhen, Kristina Young, Marka R. Crittenden, and Michael J. Gough
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Medicine ,Science - Abstract
Abstract Tissue resident memory (Trm) CD8 T cells infiltrating tumors represent an enriched population of tumor antigen-specific T cells, and their presence is associated with improved outcomes in patients. Using genetically engineered mouse pancreatic tumor models we demonstrate that tumor implantation generates a Trm niche that is dependent on direct antigen presentation by cancer cells. However, we observe that initial CCR7-mediated localization of CD8 T cells to tumor draining lymph nodes is required to subsequently generate CD103+ CD8 T cells in tumors. We observe that the formation of CD103+ CD8 T cells in tumors is dependent on CD40L but independent of CD4 T cells, and using mixed chimeras we show that CD8 T cells can provide their own CD40L to permit CD103+ CD8 T cell differentiation. Finally, we show that CD40L is required to provide systemic protection against secondary tumors. These data suggest that CD103+ CD8 T cell formation in tumors can occur independent of the two-factor authentication provided by CD4 T cells and highlight CD103+ CD8 T cells as a distinct differentiation decision from CD4-dependent central memory.
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- 2023
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3. CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden
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Sjoerd H van der Burg, Rebekka Duhen, Thomas Duhen, Marieke E Ijsselsteijn, Ruud van der Breggen, Koen C M J Peeters, Noel F C C de Miranda, Els M E Verdegaal, Dina Ruano, Manon van der Ploeg, Jitske van den Bulk, and Arantza Fariña-Sarasqueta
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Expression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8+ T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden.Experimental design Whole-exome and RNA sequencing of 11 mismatch repair-proficient (MMR-proficient) CRCs and corresponding healthy tissues were performed to determine the presence of putative neoantigens. In parallel, tumor-infiltrating lymphocytes (TILs) were cultured from the tumor fragments and, in parallel, CD8+ T cells were flow-sorted from their respective tumor digests based on single or combined expression of CD103 and CD39. Each subset was expanded and subsequently interrogated for neoantigen-directed reactivity with synthetic peptides. Neoantigen-directed reactivity was determined by flow cytometric analyses of T cell activation markers and ELISA-based detection of IFN-γ and granzyme B release. Additionally, imaging mass cytometry was applied to investigate the localization of CD103+CD39+ cytotoxic T cells in tumors.Results Neoantigen-directed reactivity was only encountered in bulk TIL populations and CD103+CD39+ (double positive, DP) CD8+ T cell subsets but never in double-negative or single-positive subsets. Neoantigen-reactivity detected in bulk TIL but not in DP CD8+ T cells could be attributed to CD4+ T cells. CD8+ T cells that were located in direct contact with cancer cells in tumor tissues were enriched for CD103 and CD39 expression.Conclusion Coexpression of CD103 and CD39 is characteristic of neoantigen-specific CD8+ T cells in MMR-proficient CRCs with low mutation burden. The exploitation of these subsets in the context of adoptive T cell transfer or engineered T cell receptor therapies is a promising avenue to extend the benefits of immunotherapy to an increasing number of CRC patients.
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- 2023
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4. OX40 agonist stimulation increases and sustains humoral and cell-mediated responses to SARS-CoV-2 protein and saRNA vaccines
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Rebekka Duhen, Michael Beymer, Shawn M. Jensen, Srinivas Abbina, Suraj Abraham, Nikita Jain, Anitha Thomas, Andrew J. Geall, Hong-Ming Hu, Bernard A. Fox, and Andrew D. Weinberg
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ANTI-OX40 ,co-stimulation ,sa-RNA vaccine ,T cell activation ,SARS-CoV-2 vaccine ,protein vaccine ,Immunologic diseases. Allergy ,RC581-607 - Abstract
To prevent SARS-CoV-2 infections and generate long-lasting immunity, vaccines need to generate strong viral-specific B and T cell responses. Previous results from our lab and others have shown that immunizations in the presence of an OX40 agonist antibody lead to higher antibody titers and increased numbers of long-lived antigen-specific CD4 and CD8 T cells. Using a similar strategy, we explored the effect of OX40 co-stimulation in a prime and boost vaccination scheme using an adjuvanted SARS-CoV-2 spike protein vaccine in C57BL/6 mice. Our results show that OX40 engagement during vaccination significantly increases long-lived antibody responses to the spike protein. In addition, after immunization spike protein-specific proliferation was greatly increased for both CD4 and CD8 T cells, with enhanced, spike-specific secretion of IFN-γ and IL-2. Booster (3rd injection) immunizations combined with an OX40 agonist (7 months post-prime) further increased vaccine-specific antibody and T cell responses. Initial experiments assessing a self-amplifying mRNA (saRNA) vaccine encoding the spike protein antigen show a robust antigen-specific CD8 T cell response. The saRNA spike-specific CD8 T cells express high levels of GrzmB, IFN-γ and TNF-α which was not observed with protein immunization and this response was further increased by the OX40 agonist. Similar to protein immunizations the OX40 agonist also increased vaccine-specific CD4 T cell responses. In summary, this study compares and contrasts the effects and benefits of both protein and saRNA vaccination and the extent to which an OX40 agonist enhances and sustains the immune response against the SARS-CoV-2 spike protein.
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- 2022
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5. PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors
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Rebekka Duhen, Olivier Fesneau, Kimberly A. Samson, Alexandra K. Frye, Michael Beymer, Venkatesh Rajamanickam, David Ross, Eric Tran, Brady Bernard, Andrew D. Weinberg, and Thomas Duhen
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Immunology ,Oncology ,Medicine - Abstract
CD4+ Th cells play a key role in orchestrating immune responses, but the identity of the CD4+ Th cells involved in the antitumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4+ Th cells distinct from FOXP3+ Tregs that coexpressed programmed cell death 1 (PD-1) and ICOS. These tumor-infiltrating lymphocyte CD4+ Th cells (CD4+ Th TILs) had a tissue-resident memory phenotype, were present in MHC class II–rich areas, and proliferated in the tumor, suggesting local antigen recognition. The T cell receptor repertoire of the PD-1+ICOS+ CD4+ Th TILs was oligoclonal, with T cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4+ Th TILs were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4+ Th TILs directly ex vivo that will help define their role in the antitumor immune response and potentially improve future adoptive T cell therapy approaches.
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- 2022
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6. Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells
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Rebekka Duhen, Carmen Ballesteros-Merino, Alexandra K. Frye, Eric Tran, Venkatesh Rajamanickam, Shu-Ching Chang, Yoshinobu Koguchi, Carlo B. Bifulco, Brady Bernard, Rom S. Leidner, Brendan D. Curti, Bernard A. Fox, Walter J. Urba, R. Bryan Bell, and Andrew D. Weinberg
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Science - Abstract
Different neoadjuvant therapies have been proposed to improve immunotherapy for cancer treatment. Here, the authors perform a phase Ib clinical trial where an agonist OX40 antibody provided prior to surgery is well tolerated and increases proliferation and activation of tumor antigen-specific T cells in head and neck cancer patients.
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- 2021
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7. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors
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Thomas Duhen, Rebekka Duhen, Ryan Montler, Jake Moses, Tarsem Moudgil, Noel F. de Miranda, Cheri P. Goodall, Tiffany C. Blair, Bernard A. Fox, Jason E. McDermott, Shu-Ching Chang, Gary Grunkemeier, Rom Leidner, Richard Bryan Bell, and Andrew D. Weinberg
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Science - Abstract
Identifying and enumerating tumor-specific CD8 T cells are important for assessing cancer prognosis and therapy efficacy. Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.
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- 2018
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8. 959 PD-1 and ICOS co-expression identifies tumor-reactive CD4 T cells in human solid tumors
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Rebekka Duhen, Olivier Fesneau, Kimberly Samson, Alexandra Frye, Michael Beymer, Venkatesh Rajamanickam, David Ross, Eric Tran, Brady Bernard, Andrew Weinberg, and Thomas Duhen
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- 2022
9. 997 T cell immunotherapies trigger neutrophils to eliminates heterogenous tumors
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Sadna Budhu, David Redmond, Jacob Ricca, Billel Gasmi, Mathieu Gigoux, Cailian Liu, Yanyun Li, Czrina Cortez, David Schroder, Arshi Arora, Travis Hollman, Lukas Kraehenbuehl, Hyejin Choi, Sara Schad, Isabell Schulze, Rebekka Duhen, Andrew Weinberg, Andrew Chow, Mikala Egeblad, Katherine Panageas, Gabrielle Rizzuto, Olivier de Henau, Aliya Holland, Jean Albrengues, Linda Hamadane, David Ng, Xue-Yan He, Jedd Wolchok, Taha Merghoub, and Daniel Hirschhorn
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- 2022
10. Abstract LB161: Single cell bioprinted cell circuits for the systematic assessment of cell-cell communication in the early tumor microenvironment
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Haylie R. Helms, Alexander E. Davies, Rebekka Duhen, Joshua M. Moreau, Ellen M. Langer, and Luiz E. Bertassoni
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Cancer Research ,Oncology - Abstract
The specific communication of multiple cell types in the tumor microenvironment plays a critical role in cancer progression. Current engineering methods have failed to adequately replicate the complexities of the tumor microenvironment (TME). In particular, generating engineered tissue-like environments with multiple TME cell types has remained challenging. Here we demonstrate the capability to pattern complex single cell circuit configurations, using a novel microfluidic bioprinting method, to study cell-cell communication in the early TME. A microfluidic dispenser (Biopixlar, Fluicell AB) was optimized to determine the delivery pressure (5 – 80 mbar), internal vacuum (0 – 80 -mbar), and external vacuum (0 – 80 -mbar) to enable highly controllable deposition of single cells suspended in complete media supplemented with polyethylene glycol (15 mg/mL, 1:1) at 1 × 106 cells/mL. Flow conditions were optimized for human cells: MDA-MB-231, MCF7, PC3, breast epithelial cells (MCF10a), fibroblasts, cancer associated fibroblasts, THP-1 derived macrophages, CD4+ T cells, CD8+ T cells, human umbilical vein endothelial cells (HUVECs), and mesenchymal stem cells. As proof of concept, the optimized settings were used to replicate a 2D tumor biopsy region of interest with high spatial precision. Next, cell-cell communication circuits were fabricated with cancer cells (PC3 or MDA-MB-231) and HUVECs. Communication circuits were bioprinted as 4 by 4 cell arrays, with 100 µm spacing between each cell, equal number of HUVECs and cancer cells, and three different cellular arrangements: alternating cell types, like cell types grouped, and groups of four like cell types. The circuits were live cell imaged for up to 30 hours to observe cell migration patterns, proliferation, and morphological changes as a function of cell-cell communication circuit arrangements. Optimal printing parameters were identified as 80 mbar delivery pressure, -25 mbar internal vacuum, and -55 mbar external vacuum. These parameters maintained >99% cell viability and ±10 µm spatial precision of printed cells. Live cell imaging of circuits containing PC3s or MDA-MB-231s with HUVECs on collagen substrates revealed changes in migration patterns, proliferation, and morphology depending on the surrounding cellular arrangement. HUVECs were highly migratory throughout the duration of the experiment, frequently extended protrusions towards nearby HUVECs, but did not display the same level of interaction with PC3s as they did with MDA-MB-231s. In MDA-MB-231 circuits, irrespective of patterning, we identified clear tendencies of HUVECs to herd MDA-MB-231s, travel overtop of MDA-MB-231s, collect and carry visible particles released from MDA-MB-231s, and maintain dendritic morphology instead of undergoing the expected vascular tubulogenesis. We found that HUVECs had the best morphology when clustered in groups of four and proliferated most when surrounded by MDA-MB-231s (alternating pattern). We found that MDA-MB-231s only proliferated when surrounded by HUVECs and had the least displacement when surrounded by like cells. These results demonstrate a method to precisely bioprint single cell circuits, enabling the investigation of cellular spatial organization and composition within the tumor microenvironment as it relates to tumor initiation and progression. Citation Format: Haylie R. Helms, Alexander E. Davies, Rebekka Duhen, Joshua M. Moreau, Ellen M. Langer, Luiz E. Bertassoni. Single cell bioprinted cell circuits for the systematic assessment of cell-cell communication in the early tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB161.
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- 2023
11. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants
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Daniel Hirschhorn, Sadna Budhu, Lukas Kraehenbuehl, Mathieu Gigoux, David Schröder, Andrew Chow, Jacob M. Ricca, Billel Gasmi, Olivier De Henau, Levi Mark B. Mangarin, Yanyun Li, Linda Hamadene, Anne-Laure Flamar, Hyejin Choi, Czrina A. Cortez, Cailian Liu, Aliya Holland, Sara Schad, Isabell Schulze, Allison Betof Warner, Travis J. Hollmann, Arshi Arora, Katherine S. Panageas, Gabrielle A. Rizzuto, Rebekka Duhen, Andrew D. Weinberg, Christine N. Spencer, David Ng, Xue-Yan He, Jean Albrengues, David Redmond, Mikala Egeblad, Jedd D. Wolchok, and Taha Merghoub
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General Biochemistry, Genetics and Molecular Biology - Published
- 2023
12. CD103 and CD39 coexpression identifies neoantigen-specific cytotoxic T cells in colorectal cancers with low mutation burden
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Jitske van den Bulk, Manon van der Ploeg, Marieke E Ijsselsteijn, Dina Ruano, Ruud van der Breggen, Rebekka Duhen, Koen C M J Peeters, Arantza Fariña-Sarasqueta, Els M E Verdegaal, Sjoerd H van der Burg, Thomas Duhen, Noel F C C de Miranda, and Pathology
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Pharmacology ,Cancer Research ,Lymphocytes, Tumor-Infiltrating ,Oncology ,Immunology ,Molecular Medicine ,Immunology and Allergy ,Immunotherapy ,Lymphocytes ,Tumor-Infiltrating ,Antigens ,CD8-Positive T-Lymphocytes ,Gastrointestinal Neoplasms - Abstract
BackgroundExpression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8+T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden.Experimental designWhole-exome and RNA sequencing of 11 mismatch repair-proficient (MMR-proficient) CRCs and corresponding healthy tissues were performed to determine the presence of putative neoantigens. In parallel, tumor-infiltrating lymphocytes (TILs) were cultured from the tumor fragments and, in parallel, CD8+T cells were flow-sorted from their respective tumor digests based on single or combined expression of CD103 and CD39. Each subset was expanded and subsequently interrogated for neoantigen-directed reactivity with synthetic peptides. Neoantigen-directed reactivity was determined by flow cytometric analyses of T cell activation markers and ELISA-based detection of IFN-γ and granzyme B release. Additionally, imaging mass cytometry was applied to investigate the localization of CD103+CD39+cytotoxic T cells in tumors.ResultsNeoantigen-directed reactivity was only encountered in bulk TIL populations and CD103+CD39+(double positive, DP) CD8+T cell subsets but never in double-negative or single-positive subsets. Neoantigen-reactivity detected in bulk TIL but not in DP CD8+T cells could be attributed to CD4+T cells. CD8+T cells that were located in direct contact with cancer cells in tumor tissues were enriched for CD103 and CD39 expression.ConclusionCoexpression of CD103 and CD39 is characteristic of neoantigen-specific CD8+T cells in MMR-proficient CRCs with low mutation burden. The exploitation of these subsets in the context of adoptive T cell transfer or engineered T cell receptor therapies is a promising avenue to extend the benefits of immunotherapy to an increasing number of CRC patients.
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- 2023
13. Agonistic Antibodies to Co-Stimulatory Molecules
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Rebekka Duhen, Alexandra K. Frye, and Andrew D. Weinberg
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- 2021
14. Tumor resident memory CD8 T cell formation and concomitant tumor immunity is CD40L dependent and CD4 independent
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Michael J Gough, Gwen Kramer, Shelly Bambina, Alejandro Alice, Tiffany Blair, Thomas Duhen, Rebekka Duhen, and Marka R Crittenden
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Immunology ,Immunology and Allergy - Abstract
The implantation of cancer cell lines into immunocompetent mice acts as a vaccination event, resulting in T cell immunity that impacts both tumor progression and the response to subsequent therapy. We have previously shown that blocking immunity at tumor implantation using anti-CD40L antibodies blocks development of an intratumoral antigen-specific CD8 T cell population with tissue resident memory (Trm) phenotypes, and also limits responsiveness to radiation therapy and immunotherapy combinations. Using pancreatic tumors derived from Pdx1-Cre and Pdx1-Cre /R26LSL-LSIY mice crossed with KrasLSL-G12D/+Tp53LSL-R172H/+ mice, we explored the role of CD4 T cells in providing CD40-CD40L help to generate Trm and conventional T central memory CD8 T cells (Tcm) cells in the tumor and systemically. Using depleting antibodies, we identified that Trm cells in the tumor could form independently of CD4 T cells but were lost following CD40L blockade. By contrast, systemically circulating Tcm cells that could re-expand after antigen-specific challenge were dependent on both CD4 T cells and CD40-CD40L interactions. Notably, concomitant immunity generated by tumor implantation that can prevent tumor growth on the opposite flank could also occur independently of CD4 T cells, but was lost on CD40L blockade. Systemic vaccination with Listeria monocytogenes expressing SIY efficiently induced the formation of SIY-specific Tcm cells but did not impact tumor implantation. These data suggest that tumor implantation generates Trm cells independently of CD4 T cells, and that these cells, not Tcm cells, sustain concomitant immunity. These data may impact immune therapies designed to control metastatic seeding in patients. Supported by grants from NIH (R01CA182311, R01CA244142, R01CA208644).
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- 2022
15. PD-1 and ICOS co-expression identifies tumor-reactive CD4 Th cells in human solid tumors
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Thomas Duhen, Rebekka Duhen, Olivier Fesneau, Kimberly Samson, Alexandra Frye, Michael Beymer, Venkatesh Rajamanickam, Eric Tran, Brady Bernard, and Andrew D Weinberg
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Immunology ,Immunology and Allergy - Abstract
CD4 T helper (Th) cells play a key role in orchestrating immune responses, but the identity of the CD4 Th cells involved in the immune response against cancer remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and microsatellite stable colorectal cancers and identified a subset of CD4 Th cells distinct from FOXP3+ regulatory T cells that co-express PD-1 and ICOS. This cell population, which was present in the tumor but absent in the periphery, features of chronic stimulation and displays characteristics of tissue-resident memory T cells. PD-1+ICOS+ tumor-infiltrating (TIL) CD4 Th cells are located primarily in the tumor stroma in proximity to MHC class II+ cells and are proliferating, suggesting local antigen recognition. The T-cell receptor repertoire of the PD-1+ICOS+ CD4 Th TIL is oligoclonal, with T-cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4 Th TIL were shown to recognize both tumor-associated antigens and tumor-specific neoantigens, which were distinct from the epitopes recognized by the CD8 T cells from the same patients. Our findings provide an approach for isolating tumor-reactive CD4 Th TIL directly ex vivo and imply that harnessing the cooperation between CD4 and CD8 T cells might lead to more efficient tumor recognition and control in cancer patients. Supported by the Providence Portland Medical Foundation and the Developmental Research Program for Head and Neck Cancer.
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- 2022
16. Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells
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Walter J. Urba, Rebekka Duhen, R. Bryan Bell, Brendan D. Curti, Shu-Ching Chang, Andrew D. Weinberg, Carmen Ballesteros-Merino, Carlo Bifulco, Yoshinobu Koguchi, Rom Leidner, Eric Tran, Brady Bernard, Alexandra K. Frye, Venkatesh Rajamanickam, and Bernard A. Fox
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0301 basic medicine ,Science ,Biopsy ,medicine.medical_treatment ,T cell ,Receptors, Antigen, T-Cell ,General Physics and Astronomy ,Cancer immunotherapy ,Kaplan-Meier Estimate ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Disease-Free Survival ,Article ,General Biochemistry, Genetics and Molecular Biology ,Epitopes ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Antigen ,medicine ,Humans ,Neoadjuvant therapy ,Cell Proliferation ,Human papillomavirus 16 ,Multidisciplinary ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Oral cancer ,Head and neck cancer ,Cancer ,General Chemistry ,Immunotherapy ,Receptors, OX40 ,medicine.disease ,Head and neck squamous-cell carcinoma ,Lymphocyte Subsets ,Neoadjuvant Therapy ,Clone Cells ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Tumour immunology ,Stromal Cells ,business ,CD8 - Abstract
Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRβ sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity., Different neoadjuvant therapies have been proposed to improve immunotherapy for cancer treatment. Here, the authors perform a phase Ib clinical trial where an agonist OX40 antibody provided prior to surgery is well tolerated and increases proliferation and activation of tumor antigen-specific T cells in head and neck cancer patients.
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- 2021
17. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors
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Shu Ching Chang, Cheri P. Goodall, Tiffany C. Blair, Bernard A. Fox, Ryan Montler, Andrew D. Weinberg, Thomas Duhen, Rebekka Duhen, Noel F C C de Miranda, Gary L. Grunkemeier, Jake Moses, Rom Leidner, R.B. Bell, Jason E. McDermott, and Tarsem Moudgil
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Male ,0301 basic medicine ,Science ,CD8 Antigens ,Receptors, Antigen, T-Cell, alpha-beta ,medicine.medical_treatment ,T cell ,General Physics and Astronomy ,Adenocarcinoma of Lung ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Immunophenotyping ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Antigen ,Antigens, CD ,medicine ,Humans ,Cytotoxic T cell ,lcsh:Science ,Melanoma ,Ovarian Neoplasms ,Multidisciplinary ,Squamous Cell Carcinoma of Head and Neck ,Apyrase ,Cancer ,hemic and immune systems ,General Chemistry ,Immunotherapy ,medicine.disease ,Survival Analysis ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Carcinoma, Squamous Cell ,Cancer research ,Female ,lcsh:Q ,Transcriptome ,Integrin alpha Chains ,CD8 - Abstract
Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies., Identifying and enumerating tumor-specific CD8 T cells are important for assessing cancer prognosis and therapy efficacy. Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.
- Published
- 2018
18. Agonistic Antibodies to Co-Stimulatory Molecules
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Rebekka Duhen and Andrew D. Weinberg
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- 2018
19. S1P
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Ahmet, Eken, Rebekka, Duhen, Akhilesh K, Singh, Mallory, Fry, Jane H, Buckner, Mariko, Kita, Estelle, Bettelli, and Mohamed, Oukka
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Inflammation ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Transcription, Genetic ,Fingolimod Hydrochloride ,Lymphoid Tissue ,Lymphadenopathy ,chemical and pharmacologic phenomena ,hemic and immune systems ,Autoimmunity ,T-Lymphocytes, Regulatory ,Article ,Mice, Inbred C57BL ,Mice ,Receptors, Lysosphingolipid ,Phenotype ,Organ Specificity ,Case-Control Studies ,Animals ,Humans ,Th17 Cells ,Disease Susceptibility ,Gene Deletion - Abstract
Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P1 in Treg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P1 not only regulated the egress of Treg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the Treg cells found in S1P1-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector Treg. Our results provide novel insight into the functions of S1P1 and potential impact of long term fingolimod use on Th17 and Treg cell biology and general health in MS patients.
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- 2016
20. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one
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Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. 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Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. 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Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. 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Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle
- Subjects
Pharmacology ,0303 health sciences ,Cancer Research ,Side effect ,business.industry ,medicine.drug_class ,Immunology ,Phases of clinical research ,Monoclonal antibody ,Phase i study ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunology and Allergy ,Medicine ,In patient ,Programmed death 1 ,business ,030304 developmental biology - Published
- 2016
21. Abstract B094: Successful identification of neoantigen-specific T-cell responses in low mutation burden colorectal cancers for personalized cancer vaccine development
- Author
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Sjoerd H. van der Burg, Els M. E. Verdegaal, Thomas Duhen, Noel F C C de Miranda, Marten Visser, Andrew D. Weinberg, Ruud van der Breggen, Dina Ruano, Rebekka Duhen, Marieke E. Ijsselsteijn, Jitske van den Bulk, and Koen C.M.J. Peeters
- Subjects
Cancer Research ,integumentary system ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Immunology ,Cancer ,Human leukocyte antigen ,medicine.disease ,Immune checkpoint ,Immune system ,Antigen ,Cancer immunotherapy ,Cancer research ,Medicine ,Cancer vaccine ,business - Abstract
Innovative treatment options are required to improve cure rates in advanced colorectal cancer patients. Immune checkpoint blockade therapy (anti-PD-1) was shown to be effective in colorectal cancers with high mutation burden (e.g., mismatch repair deficient) as antitumor reactivity is largely explained by the recognition of somatically mutated antigens (neoantigens). No immunotherapeutic strategies are currently available for patients diagnosed with low mutation burden colorectal cancer. We hypothesized that if neoantigen-reactive T-cells are present in low mutation burden patients, the latter could benefit from immunotherapeutic interventions that stimulate neoantigen recognition and the onset of a robust antitumor immune response.In order to detect neoantigens, whole exome and RNA next-generation sequencing analyses were performed in cancer and healthy tissues from five colorectal cancer patients. Corresponding neoepitopes were synthesized and tested for their ability to induce immune cell activation in T-cells isolated from the tumor tissue (TIL) and from peripheral blood. Neoantigen-specific T-cell responses were identified in the majority of patients that presented with tumors carrying 25 to 36 transcribed, non-synonymous variants. Up to six different neoantigens were recognized per tumor, which resulted in a higher detection rate than anticipated based on published data. Moreover, we discovered the merits of isolating CD39+CD103+CD8+ T-cells for detection of a broad recognition of HLA class I-restricted neoantigens. This CD39+CD103+CD8+ T-cell subset comprises the majority and a broader repertoire of neoantigen-specific T-cells compared to bulk TIL populations or lymphocytes derived from peripheral blood. In conclusion, we developed a neoantigen screening pipeline to unlock the immunogenic potential of colorectal cancers with low mutation burden. We have detected a relatively high number of neoantigens that are recognized by tumor- and/or PBMC-derived T-cells in mismatch repair proficient, low mutation burden colorectal cancer patients, and show the importance of the CD39+CD103+CD8+ T-cell subset for neoantigen-based immunotherapies. These findings warrant the further exploration of the potential to employ neoantigen-targeted therapies to improve clinical outcomes of colorectal cancer patients. Citation Format: Jitske van den Bulk, Dina Ruano, Marieke E. Ijsselsteijn, Marten Visser, Ruud van der Breggen, Koen C.M.J. Peeters, Thomas Duhen, Rebekka Duhen, Andrew D Weinberg, Sjoerd S.H. van der Burg, Els M.E. Verdegaal, Noel F. de Miranda. Successful identification of neoantigen-specific T-cell responses in low mutation burden colorectal cancers for personalized cancer vaccine development [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B094.
- Published
- 2019
22. Abstract A186: A new strategy to identify and expand tumor-reactive CD8 TILs in human solid tumors
- Author
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Thomas Duhen, Noel F C C de Miranda, Els M. E. Verdegaal, Rom Leidner, Gary L. Grunkemeier, Jitske van den Bulk, Tarsem Moudgil, Bernard A. Fox, Richard Bryan Bell, Rebekka Duhen, Ryan Montler, Andrew D. Weinberg, and Shu-Ching Chang
- Subjects
Cancer Research ,education.field_of_study ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Melanoma ,Immunology ,Head and neck cancer ,Population ,Cancer ,hemic and immune systems ,chemical and pharmacologic phenomena ,Immunotherapy ,medicine.disease ,Metastasis ,Cancer immunotherapy ,medicine ,Cancer research ,business ,education - Abstract
The immune system can recognize and destroy tumor cells through T-cell mediated mechanisms. Hence, identifying tumor antigen-specific T-cells from cancer patients and expanding them in large numbers in vitro has important implications for immunotherapy diagnostics and therapeutics. Here we show that tumor-reactive T-cells are enriched in a subset of tumor-infiltrating CD8 T-cells (CD8 TILs) identified by co-expression of CD103 and CD39 both in primary and metastatic tumors. The CD103+CD39+ CD8 TILs are present at high frequencies in melanoma and mismatch repair-deficient colon cancer but at low frequencies in microsatellite stable (MSS) colon cancer and colorectal liver metastasis. This cell population displays a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. Importantly, we show in a MSS colon cancer patient that a very low number of CD103+CD39+ CD8 TILs can be expanded in vitro and that those cells recognize tumor-specific neoantigens. Finally, patients with head and neck cancer whose CD8 TILs contained a higher frequency of CD103+CD39+ cells experienced a greater overall survival. Our work suggests that CD103+CD39+ CD8 TILs are key players in the patient’s antitumor response and describe an approach for detecting and expanding those cells, which will help improve adoptive TIL therapy for cancer patients. Citation Format: Thomas Duhen, Rebekka Duhen, Ryan Montler, Tarsem Moudgil, Jitske van den Bulk, Bernard A. Fox, Shu-Ching Chang, Gary Grunkemeier, Els M.E. Verdegaal, Noel F. de Miranda, Rom Leidner, Richard B. Bell, Andrew D. Weinberg. A new strategy to identify and expand tumor-reactive CD8 TILs in human solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A186.
- Published
- 2019
23. S1P(1) deletion differentially affects TH17 and regulatory T cells
- Author
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Mariko Kita, Ahmet Eken, Akhilesh Kumar Singh, Mallory Fry, Rebekka Duhen, Estelle Bettelli, Jane H. Buckner, and Mohamed Oukka
- Subjects
0301 basic medicine ,Encephalomyelitis ,Immunology ,lcsh:Medicine ,chemical and pharmacologic phenomena ,Biology ,medicine.disease_cause ,Autoimmunity ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Receptor ,lcsh:Science ,Multidisciplinary ,Experimental autoimmune encephalomyelitis ,lcsh:R ,FOXP3 ,hemic and immune systems ,medicine.disease ,Fingolimod ,3. Good health ,030104 developmental biology ,Apoptosis ,Cancer research ,Experimental pathology ,lcsh:Q ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P1 in Treg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P1 not only regulated the egress of Treg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the Treg cells found in S1P1-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector Treg. Our results provide novel insight into the functions of S1P1 and potential impact of long term fingolimod use on Th17 and Treg cell biology and general health in MS patients.
- Published
- 2016
24. Cutting Edge: Loss of α4 Integrin Expression Differentially Affects the Homing of Th1 and Th17 Cells
- Author
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Estelle Bettelli, Mohamed Oukka, Rebekka Duhen, and Simon Glatigny
- Subjects
biology ,Cellular differentiation ,Encephalomyelitis ,Immunology ,Experimental autoimmune encephalomyelitis ,Integrin ,medicine.disease ,CD49b ,Cell biology ,Immune system ,Integrin alpha M ,medicine ,biology.protein ,Immunology and Allergy ,Homing (hematopoietic) - Abstract
The neutralization of α4 integrin is currently used as treatment in several autoimmune diseases and is thought to prevent the entry of most immune cells in target tissues. In this study, we showed that selective deletion of α4 integrin in T cells did not prevent but delayed the development of experimental autoimmune encephalomyelitis. Whereas both Th1 and Th17 cells infiltrate the CNS of wild-type mice, T cells present in the CNS of mice lacking α4 integrin were mainly enriched in Th17 cells, suggesting that this T cell subset uses other integrins to access the CNS. In contrast, α4 integrin expression is important for Th1 cells to enter the CNS and for the stability of their Th1-associated genetic program. Therefore, our data suggest that anti-α4 integrin Ab treatment may be more efficient in the treatment of Th1- rather than Th17-mediated disease.
- Published
- 2011
25. Neoadjuvant anti-OX40 (MEDI6469) prior to surgery in head and neck squamous cell carcinoma
- Author
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Allen C. Cheng, Carlo Bifulco, Walter J. Urba, Rebekka Duhen, Bernard A. Fox, Ashish A. Patel, Joanna Pucilowska, Brendan D. Curti, Carmen Ballesteros-Merino, Yoshinobu Koguchi, Thomas Duhen, Brady Bernard, William L. Redmond, Andrew D. Weinberg, Brian D. Piening, Rom Leidner, Mark W. Schuster, Richard Bryan Bell, George Morris, and Raina Tamakawa
- Subjects
0301 basic medicine ,Surgical resection ,Cancer Research ,medicine.medical_specialty ,business.industry ,Murine antibody ,medicine.disease ,Head and neck squamous-cell carcinoma ,Surgery ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,In patient ,business - Abstract
6011Background: This phase Ib clinical trial was performed to investigate an agonistic murine antibody to OX40 (MEDI6469) at various dose intervals prior to definitive surgical resection in patient...
- Published
- 2018
26. Abstract 37: Anti-OX40 (MEDI6469) prior to definitive surgical resection in patients with head and neck squamous cell carcinoma
- Author
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Andrew D. Weinberg, Brendan D. Curti, R. Bryan Bell, Rebekka Duhen, Zipei Feng, Bernard A. Fox, Carlo Bifulco, Walter J. Urba, Carmen Ballesteros-Merino, Yoshinobu Koguchi, and Rom Leidner
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,Tumor microenvironment ,medicine.medical_specialty ,business.industry ,Tumor-infiltrating lymphocytes ,T cell ,Head and neck cancer ,FOXP3 ,Cancer ,medicine.disease ,Primary tumor ,Head and neck squamous-cell carcinoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business - Abstract
Background: Head and neck squamous cell carcinomas (HNSCC) produce suppressive factors that impair the immune system, thus limiting effective antitumor immunity. OX40 is a member of the tumor necrosis factor (TNF) receptor family and its biologic activity leads to potent co-stimulation, which can enhance T-cell memory, proliferation and antitumor activity in patients with metastatic cancer. However, its effect on wound healing and the optimal timing of administration in relation to surgery to induce immune changes within the tumor microenvironment (TME) is not known. Objectives: To determine the safety and peak immunologic activity of neoadjuvant anti-OX40 treatment administered prior to definitive surgical resection in patients with locoregionally advanced HNSCC. Methods: Between January 2016 and July 2016, 10 patients with locoregionally advanced HNSCC were enrolled into this phase Ib neoadjuvant time course trial testing a murine antibody to OX40 (MEDI6469) administered 2 days, 1 week and 2 weeks prior to definitive surgical resection. In order to assess changes in the tumor microenvironment (TME), a tissue biopsy and peripheral blood samples were obtained prior to MEDI6469 infusion and tissue was also harvested at the time of surgical resection from the primary tumor site, metastatic and draining lymph nodes along with peripheral blood. Assessments of tumor infiltrating lymphocyte (TIL) populations were performed based on flow cytometry and fluorescent multiplex immunohistochemistry (mIHC); other circulating immunologic parameters that correlate with changes induced by MEDI6469 administration were also measured. These immune changes were assessed and compiled in a “cumulative suppression index,” which incorporates immunosuppressive elements within the tumor, such as FoxP3+ and PD-L1+ cells, to be correlated with clinical variables and outcome. Surgical complications were described using the Clavien-Dindo grading scale. Clinical trial information: NCT02274155. Results: MEDI6469 administration was well tolerated and there were no grade 3 or 4 adverse events (AEs) attributable to anti-OX40 treatment. The toxicity profile was mild, most commonly consisting of low-grade fever prior to surgery, which was performed in all patients without delay. Postoperative grade 3 and 4 complications per Clavien-Dindo scale were observed in two patients. Immunologic changes were observed at all time courses with significant activation and proliferation of CD4+ and CD8+ central and effector memory T-cell populations in both the TME and circulation occurring between 12 and 19 days following MEDI6469 infusion. Ki67 was specifically induced in the TME and on peripheral blood PBMCs after MEDI6469 administration, returning to baseline at Day 55. Up-regulation of PD-L1 was also seen in the tumor post treatment in the majority of specimens. In the tumor, expression of CD39, ICOS and PD-1 is increased on CD4+ T cells in almost all patients and a recently identified tumor-reactive T-cell subset of CD39+CD103+CD8+ T cells, with resident memory phenotype, was increased in some patients. Conclusion: Preoperative MEDI6469 administration prior to surgery is feasible and safe in patients with HNSCC and results in activation and proliferation of T cell populations and up-regulation of PD-L1 in tumor cells occurring between 12 and 19 days following infusion. Citation Format: R. Bryan Bell, Rom S. Leidner, Rebekka A. Duhen, Carmen Ballesteros-Merino, Zipei Feng, Yoshinobu Koguchi, Carlo B. Bifulco, Brendan D. Curti, Walter J. Urba, Bernard A. Fox, Andrew D. Weinberg. Anti-OX40 (MEDI6469) prior to definitive surgical resection in patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 37.
- Published
- 2017
27. Integrin alpha L controls the homing of regulatory T cells during CNS autoimmunity in the absence of integrin alpha 4
- Author
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Swarnima Kumari, Estelle Bettelli, Carlos A. Arbelaez, Rebekka Duhen, and Simon Glatigny
- Subjects
Central Nervous System ,Encephalomyelitis, Autoimmune, Experimental ,Cellular differentiation ,Encephalomyelitis ,Integrin alpha4 ,Integrin Alpha-L ,chemical and pharmacologic phenomena ,Autoimmunity ,Biology ,medicine.disease_cause ,Real-Time Polymerase Chain Reaction ,T-Lymphocytes, Regulatory ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Lymphocyte function-associated antigen 1 ,CD11a Antigen ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,hemic and immune systems ,Cell Differentiation ,Forkhead Transcription Factors ,Th1 Cells ,medicine.disease ,Lymphocyte Function-Associated Antigen-1 ,Mice, Inbred C57BL ,Immunology ,Th17 Cells ,030217 neurology & neurosurgery ,Homing (hematopoietic) - Abstract
Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), results from an autoimmune attack of the central nervous system (CNS) by effector T helper (Th) 1 and Th17 cells. Regulatory T cells (Treg) can control effector T cells and limit the progression of CNS autoimmunity. Integrin alpha 4 (Itga4) is critical for the entry of Th1 but not Th17 cells into the CNS during EAE. Whether Itga4 controls the homing of Tregs in the CNS and whether Tregs can limit Th17-mediated EAE has, however, not been addressed. Through selective elimination of Itga4 in Foxp3-expressing cells, we show here that Tregs can suppress Th17-mediated EAE and enter into the CNS independently of Itga4. Furthermore, similarly to Th17 cells and in contrast to Th1 cells, Tregs depend on LFA-1 for their entry into the CNS in the absence of Itga4. Therefore, these data suggest that the efficacy of Itga4 neutralization on MS progression may be associated with the prevention of Th1 cells and the maintenance of Tregs migration into the CNS.
- Published
- 2015
28. IL-7/IL-7 Receptor Signaling Differentially Affects Effector CD4+ T Cell Subsets Involved in Experimental Autoimmune Encephalomyelitis
- Author
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Mohamed Oukka, Carlos A. Arbelaez, Simon Glatigny, Estelle Bettelli, Rebekka Duhen, and Gérard Eberl
- Subjects
CD4-Positive T-Lymphocytes ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,T cell ,Immunology ,Mice, Transgenic ,Biology ,Interleukin-23 ,Article ,Interleukin 21 ,Interferon-gamma ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,IL-2 receptor ,Antigen-presenting cell ,Cells, Cultured ,Mice, Knockout ,Receptors, Interleukin-7 ,ZAP70 ,Interleukin-7 ,Cell Differentiation ,Receptors, Interleukin ,Th1 Cells ,Natural killer T cell ,Flow Cytometry ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Interleukin 12 ,Th17 Cells ,Signal Transduction - Abstract
IL-17–producing CD4+ T (Th17) cells, along with IFN-γ–expressing Th1 cells, represent two major pathogenic T cell subsets in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). The cytokines and transcription factors involved in the development and effector functions of Th1 and Th17 cells have been largely characterized. Among them, IL-23 is essential for the generation of stable and encephalitogenic Th17 cells and for the development of EAE. The IL-7/IL-7R signaling axis participates in cell survival, and perturbation of this pathway has been associated with enhanced susceptibility to MS. A link between IL-23–driven pathogenic T cells and IL-7/IL-7R signaling has previously been proposed, but has not been formally addressed. In the current study, we showed that Th17 cells from mice with EAE express high levels of IL-7Rα compared with Th1 cells. Using mice that constitutively express IL-7Rα on T cells, we determined that sustained IL-7R expression in IL-23R–deficient mice could not drive pathogenic T cells and the development of EAE. IL-7 inhibited the differentiation of Th17 cells, but promoted IFN-γ and GM-CSF secretion in vitro. In vivo IL-7/anti–IL-7 mAb complexes selectively expanded and enhanced the proliferation of CXCR3-expressing Th1 cells, but did not impact Th17 cells and EAE development in wild-type and IL-23R–deficient mice. Importantly, high IL-7 expression was detected in the CNS during EAE and could drive the plasticity of Th17 cells to IFN-γ–producing T cells. Together, these data address the contribution of IL-23/IL-23R and IL-7/IL-7R signaling in Th17 and Th1 cell dynamics during CNS autoimmunity.
- Published
- 2014
29. Cutting edge: the pathogenicity of IFN-γ-producing Th17 cells is independent of T-bet
- Author
-
Rebekka Duhen, Carlos A. Arbelaez, Simon Glatigny, Mohamed Oukka, Estelle Bettelli, and Tiffany C. Blair
- Subjects
Encephalomyelitis, Autoimmune, Experimental ,Immunology ,chemical and pharmacologic phenomena ,Interleukin-23 ,Article ,Myelin oligodendrocyte glycoprotein ,Myelin ,Interferon-gamma ,Mice ,medicine ,Immunology and Allergy ,Animals ,STAT4 ,Interleukin 3 ,biology ,Experimental autoimmune encephalomyelitis ,Interleukin-17 ,hemic and immune systems ,STAT4 Transcription Factor ,Th1 Cells ,medicine.disease ,Oligodendrocyte ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,STAT1 Transcription Factor ,Interleukin 12 ,Cancer research ,biology.protein ,Th17 Cells ,Myelin-Oligodendrocyte Glycoprotein ,Interleukin 17 ,T-Box Domain Proteins - Abstract
During the development of experimental autoimmune encephalomyelitis (EAE), the proportion of pathogenic and myelin-specific cells within CNS-infiltrating cytokine-producing Th cells is unknown. Using an IL-17A/IFN-γ double reporter mouse and I-Ab/myelin oligodendrocyte glycoprotein 38–49 tetramer, we show in this study that IL-17+IFN-γ+ Th cells, which are expanded in the CNS during EAE, are highly enriched in myelin oligodendrocyte glycoprotein–specific T cells. We further demonstrate that IL-23 is essential for the generation and expansion of IFN-γ–producing Th17 cells independently of the Th1-associated transcription factors T-bet, STAT1, and STAT4. Furthermore, Th17 and IL-17+IFN-γ+ Th cells can induce CNS autoimmunity independently of T-bet. Whereas T-bet is crucial for Th1-mediated EAE, it is dispensable for Th17 cell–mediated autoimmunity. Our results suggest the existence of different epigenetic programs that regulate IFN-γ expression in Th1 and Th17 cells.
- Published
- 2013
30. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells
- Author
-
Federica Sallusto, Rebekka Duhen, Antonio Lanzavecchia, Thomas Duhen, and Daniel J. Campbell
- Subjects
CD4-Positive T-Lymphocytes ,Immunology ,Population ,Anti-Inflammatory Agents ,chemical and pharmacologic phenomena ,T-Cell Antigen Receptor Specificity ,Biology ,Biochemistry ,T-Lymphocytes, Regulatory ,Chemokine receptor ,Interleukin 21 ,Immune system ,Antigen ,Cytotoxic T cell ,Humans ,IL-2 receptor ,education ,Cells, Cultured ,Immunobiology ,education.field_of_study ,FOXP3 ,Forkhead Transcription Factors ,Cell Biology ,Hematology ,T-Lymphocytes, Helper-Inducer ,Phenotype ,Cytokines ,Inflammation Mediators ,Transcription Factors - Abstract
FOXP3+ regulatory T (Treg) cells are a broadly acting and potent anti-inflammatory population of CD4+ T cells essential for maintaining immune homeostasis and preventing debilitating autoimmunity. Based on chemokine receptor expression, we identified distinct populations of Treg cells in human blood expected to colocalize with different Th cell subsets. Although each population was functionally suppressive, they displayed unique patterns of pro- and anti-inflammatory cytokine production, differentially expressed lineage-specifying transcription factors, and responded differently to antigens associated with Th1 and Th17 responses. These results highlight a previously unappreciated degree of phenotypic and functional diversity in human Treg cells that allows subsets with unique specificities and immunomodulatory functions to be targeted to defined immune environments during different types of inflammatory responses.
- Published
- 2012
31. Integrin alpha 4 differentially affect the migration of effector and regulatory T cells (P4113)
- Author
-
Estelle Bettelli, Simon Glatigny, Rebekka Duhen, Carlos Arbelaez, Swarnima Kumari, and Mohamed Oukka
- Subjects
Immunology ,Immunology and Allergy - Abstract
The integrin alpha 4 (Itga4) is expressed on immune cells and is an important molecule for the migration of T cells in various organs. Because of this propriety, a monoclonal antibody specific to Itga4 is used for the treatment of multiple sclerosis (MS). Although effective, anti-Itga4 therapy has been associated with the development of progressive multifocal leukoencephalopathy (PML), a life threatening condition, which results from a rare infection of the central nervous system (CNS) by the JC virus. Despite its use and efficacy in the clinic, it remains unclear how different cells of the adaptive immune system are affected by Itga4 deletion or neutralization. Experimental autoimmune encephalomyelitis (EAE) serves as an animal model of multiple sclerosis (MS). It results from an autoimmune attack by myelin reactive effector T helper (Th) 1 and Th17 cells and progressive demyelination. Foxp3+ regulatory T cells can control effector T cell responses but are not always effective during autoimmune disease progression. Using mice with selective deletion of Itga4 in T cells, we previously reported that Itga4 selectively inhibits the migration of Th 1 cells but not Th17 cells in the CNS. We have now established that Itga4 differentially affect the migration of effector and regulatory T cells during EAE. The implication of our findings for MS therapy will be discussed.
- Published
- 2013
32. Pathogenicity of IFN-γ+ Th17 cells is independent of T-bet (P4128)
- Author
-
Rebekka Duhen, Simon Glatigny, Carlos Arbelaez, Tiffany Blair, Mohamed Oukka, and Estelle Bettelli
- Subjects
Immunology ,Immunology and Allergy - Abstract
It is now established that T helper (Th) cell subsets, particularly Th17 cells, are more dynamic than originally anticipated and can acquire the expression of other lineage effector cytokines. However, the molecular cues that dictate their plasticity are unknown. We show that IL-23 plays a central role in the plasticity of Th17 cells and is essential for the generation and propagation of IFN-γ-producing Th17 (IL-17+ IFN-γ+) cells. During the development of experimental autoimmune encephalomyelitis (EAE) IL-17+ IFN-γ+ T cells are preferentially expanded in the central nervous system (CNS). Using an IL-17A-IFN-γ double reporter mouse and I-Ab/MOG38-49 tetramer, we determined that they displayed characteristics of pathogenic T cells, such as GM-CSF expression, and contained the highest number of MOG-specific T cells. Interestingly, the Th1-associated transcription factors T-bet, STAT1 and STAT4 were not involved in the induction of IFN-γ by Th17 cells in vitro. Moreover, in contrast to previous studies showing a role for T-bet in Th1 and Th17-mediated EAE, we demonstrate that T-bet expression in T cells is not required for the emergence of CNS-infiltrating IL-17+ IFN-γ+ T cells and the development of Th17-driven EAE. Our results suggest the existence of different epigenetic programs that regulate IFN-γ expression in Th1 and Th17 cells.
- Published
- 2013
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