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1. Cisplatin-based chemoradiation decreases telomerase-specific CD4 TH1 response but increases immune suppressive cells in peripheral blood

Author

Jihane Boustani, Elodie Lauret Marie Joseph, Etienne Martin, Salim Benhmida, Benoit Lecoester, Florent Tochet, Céline Mirjolet, Cédric Chevalier, David Thibouw, Noémie Vulquin, Stéphanie Servagi, Xushan Sun, and Olivier Adotévi

Subjects
Chemoradiation, Immune suppressive cells, Tumor-specific T cell response, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background The synergistic effect of chemoradiation (CRT) has been previously demonstrated in several cancer types. Here, we investigated the systemic immune effects of CRT in patients with lung or head and neck cancer. Materials and methods Peripheral blood mononuclear cells were collected at baseline and 1 month after treatment from blood samples of 29 patients treated with cisplatin-based chemoradiotherapy for lung or head and neck cancer. Circulating anti-tumor Th1 response was assessed by the ELISpot assay using a mixture of human leucocyte antigen (HLA) class II restricted peptides derived from telomerase (TERT). Phenotyping of circulating immunosuppressive cells (Treg and MDSC) was performed by flow cytometry. Results A significant increase of circulating Treg was observed in 60% of patients after CRT The mean rate of Treg was 3.1% versus 4.9% at baseline and after CRT respectively, p = 0.0015). However, there was a no significant increase of MDSC rate after CRT. In contrast, a decrease of tumor-specific Th1 response was documented in 7 out of 10 evaluated patients. We found high frequency of pre-existing tumor-specific Th1 response among patients with objective response after CRT compared to non-responders. Conclusion Cisplatin-based CRT promotes expansion of Treg and decrease of circulating anti-tumor Th1 response in peripheral blood. The balance towards a sustained specific anti-tumor T-cell response appears to be associated with response to CRT.

Published
2021
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2. Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy

Author

Florence Marliot, Marc Van den Eynde, Franck Pagès, Romain Boidot, Céline Mirjolet, Amos Kirilovsky, Carine El Sissy, Nacilla Haicheur-Adjouri, Viorel Scripcariu, Olivier Adotevi, Laurie Spehner, Elodie Lauret Marie Joseph, Benoît Lecoester, Laura Boullerot, Laurie Rangan, Amélie Marguier, Florent Tochet, Magalie Dosset, Jihane Boustani, Patrice Ravel, Jean-René Pallandre, Francis Bonnefoy, and Emmanuel Cornillot

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Multiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.Methods This study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining.Results Front-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity.Conclusions Our results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.

Published
2021
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3. Circulating NKp46+ Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer

Author

Emilie Picard, Yann Godet, Caroline Laheurte, Magalie Dosset, Jeanne Galaine, Laurent Beziaud, Romain Loyon, Laura Boullerot, Elodie Lauret Marie Joseph, Laurie Spehner, Marion Jacquin, Guillaume Eberst, Béatrice Gaugler, Françoise Le pimpec-Barthes, Elizabeth Fabre, Virginie Westeel, Anne Caignard, Christophe Borg, and Olivier Adotévi

Subjects
nk cells, nsclc, nkp46, cd16, prognosis, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56dim CD16+ NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56bright NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56dim CD16− phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56dim CD16− NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46+ NK cell subsets was absent in HD. We showed that the rate of circulating NKp46+ CD56dim CD16+ NK cells influenced the patients’ survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46+ NK cell subset in NSCLC patients.

Published
2019
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7. Data from Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non–Small Cell Lung Cancer

Author

Olivier Adotévi, Christophe Borg, Magalie Dosset, Laurie Rangan, Adeline Bouard, Eléonore Gravelin, Kamal Asgarov, Laura Boullerot, Marine Jary, Caroline Laheurte, and Elodie Lauret Marie Joseph

Abstract

Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non–small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.

Published
2023
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8. Supplementary Figure S5 from Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Author

Olivier Adotévi, Yann Godet, Christophe Borg, Xavier Pivot, Antoine Thiery-Vuillemin, Eric Tartour, Jagadeesh Bayry, Béatrice Gaugler, Bernard Royer, Elsa Curtit, Thierry Nguyen Tan Hon, Guillaume Mouillet, Tristan Maurina, Lise Queiroz, Sindy Vrecko, Clémentine Gamonet, Laura Boullerot, Jean-René Pallandre, Francis Bonnefoy, Laurie Rangan, Caroline Laheurte, Elodie Lauret Marie-Joseph, Patrice Ravel, Laura Mansi, and Laurent Beziaud

Abstract

This file contains contains CD8 responses in immune groups: Supplementary figure 5

Published
2023
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9. Supplementary Table S1 from Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Author

Olivier Adotévi, Yann Godet, Christophe Borg, Xavier Pivot, Antoine Thiery-Vuillemin, Eric Tartour, Jagadeesh Bayry, Béatrice Gaugler, Bernard Royer, Elsa Curtit, Thierry Nguyen Tan Hon, Guillaume Mouillet, Tristan Maurina, Lise Queiroz, Sindy Vrecko, Clémentine Gamonet, Laura Boullerot, Jean-René Pallandre, Francis Bonnefoy, Laurie Rangan, Caroline Laheurte, Elodie Lauret Marie-Joseph, Patrice Ravel, Laura Mansi, and Laurent Beziaud

Abstract

This file contains the patients characteristics: Supplementary table 1

Published
2023
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10. Supplementary figure legends from Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Author

Olivier Adotévi, Yann Godet, Christophe Borg, Xavier Pivot, Antoine Thiery-Vuillemin, Eric Tartour, Jagadeesh Bayry, Béatrice Gaugler, Bernard Royer, Elsa Curtit, Thierry Nguyen Tan Hon, Guillaume Mouillet, Tristan Maurina, Lise Queiroz, Sindy Vrecko, Clémentine Gamonet, Laura Boullerot, Jean-René Pallandre, Francis Bonnefoy, Laurie Rangan, Caroline Laheurte, Elodie Lauret Marie-Joseph, Patrice Ravel, Laura Mansi, and Laurent Beziaud

Abstract

This file contains the legends for the supplementary figures

Published
2023
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11. Data from Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Author

Olivier Adotévi, Yann Godet, Christophe Borg, Xavier Pivot, Antoine Thiery-Vuillemin, Eric Tartour, Jagadeesh Bayry, Béatrice Gaugler, Bernard Royer, Elsa Curtit, Thierry Nguyen Tan Hon, Guillaume Mouillet, Tristan Maurina, Lise Queiroz, Sindy Vrecko, Clémentine Gamonet, Laura Boullerot, Jean-René Pallandre, Francis Bonnefoy, Laurie Rangan, Caroline Laheurte, Elodie Lauret Marie-Joseph, Patrice Ravel, Laura Mansi, and Laurent Beziaud

Abstract

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes+CD8+ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100–12. ©2016 AACR.

Published
2023
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12. Supplementary methods from Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Author

Olivier Adotévi, Yann Godet, Christophe Borg, Xavier Pivot, Antoine Thiery-Vuillemin, Eric Tartour, Jagadeesh Bayry, Béatrice Gaugler, Bernard Royer, Elsa Curtit, Thierry Nguyen Tan Hon, Guillaume Mouillet, Tristan Maurina, Lise Queiroz, Sindy Vrecko, Clémentine Gamonet, Laura Boullerot, Jean-René Pallandre, Francis Bonnefoy, Laurie Rangan, Caroline Laheurte, Elodie Lauret Marie-Joseph, Patrice Ravel, Laura Mansi, and Laurent Beziaud

Abstract

This file contains the supplementary material and methods

Published
2023
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13. Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non–Small Cell Lung Cancer

Author

Caroline Laheurte, Laura Boullerot, Olivier Adotevi, L. Rangan, Magalie Dosset, Elodie Lauret Marie Joseph, Marine Jary, Adeline Bouard, Eléonore Gravelin, Christophe Borg, and Kamal Asgarov

Subjects
0301 basic medicine, Cancer Research, business.industry, medicine.medical_treatment, Immunology, Immunosuppression, Immunotherapy, medicine.disease, Immune tolerance, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, Antigen, Cancer immunotherapy, 030220 oncology & carcinogenesis, cardiovascular system, medicine, Cancer research, Carcinoma, Lung cancer, business
Abstract

Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non–small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.

Published
2020
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14. Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

Author

Patrice Ravel, Elodie Lauret Marie-Joseph, Laura Boullerot, Laura Mansi, Laurent Beziaud, Ludger Johannes, Olivier Adotevi, Thi Tran, Jagadeesh Bayry, and Eric Tartour

Subjects
0301 basic medicine, Cancer Research, business.industry, Melanoma, Cancer, medicine.disease, Temsirolimus, 3. Good health, Vaccination, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, Cytotoxic T cell, business, Interleukin-7 receptor, PI3K/AKT/mTOR pathway, CD8, medicine.drug
Abstract

mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127+ CD62L+ ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (Tregs ) expansion in vivo limits the efficacy of the bi-therapy by altering the antitumor CD8 T-cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent Tregs induction considerably improved the efficacy of the bi-therapy by enhancing CD8 T cells-mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit Tregs .

Published
2018
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15. Identification of a novel PD-L1 positive solid tumor transplantable in HLA-A*0201/DRB1*0101 transgenic mice

Author

Elodie Lauret Marie Joseph, Séverine Valmary-Degano, Romain Boidot, Jean-René Pallandre, Olivier Adotevi, Yann Godet, Mohamad Hamieh, Jean Baptiste Latouche, Christophe Borg, Talal Al Saati, Jeanne Galaine, L. Rangan, Afag Asgarova, Laurent Beziaud, Magalie Dosset, Julie Francoual, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Plateforme de transfert en biologie cancérologique [Dijon], Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), UPS CREFRE US006, Service d'Histopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [CHU Besançon], Hôpital Jean Minjoz, université de Bourgogne, LNC, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Université Bourgogne Franche-Comté ( UBFC ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques ( GPMCND ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), and Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz [Besançon]

Subjects
Male, 0301 basic medicine, sarcoma, medicine.medical_treatment, Gene Expression, Apoptosis, B7-H1 Antigen, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, Monoclonal antibody therapy, biology, 3. Good health, Oncology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Research Paper, PD-L1, Genetically modified mouse, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, T cells, Antineoplastic Agents, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Cell Line, Tumor, HLA-A2 Antigen, HLA transgenic mouse, medicine, Animals, Humans, Tumor microenvironment, cancer immunotherapy, business.industry, Gene Expression Profiling, Disease Models, Animal, 030104 developmental biology, Cell culture, Immunology, biology.protein, Cancer research, business, HLA-DRB1 Chains
Abstract

IF 5.168; International audience; HLA-A*0201/DRB1*0101 transgenic mice (A2/DR1 mice) have been developed to study the immunogenicity of tumor antigen-derived T cell epitopes. To extend the use and application of this mouse model in the field of antitumor immunotherapy, we described a tumor cell line generated from a naturally occurring tumor in A2/DR1 mouse named SARC-L1. Histological and genes signature analysis supported the sarcoma origin of this cell line. While SARC-L1 tumor cells lack HLA-DRB1*0101 expression, a very low expression of HLA-A*0201 molecules was found on these cells. Furthermore they also weakly but constitutively expressed the programmed death-ligand 1 (PD-L1). Interestingly both HLA-A*0201 and PD-L1 expressions can be increased on SARC-L1 after IFN-γ exposure in vitro. We also obtained two genetically modified cell lines highly expressing either HLA-A*0201 or both HLA-A*0201/ HLA-DRB1*0101 molecules referred as SARC-A2 and SARC-A2DR1 respectively. All the SARC-L1-derived cell lines induced aggressive subcutaneous tumors in A2DR1 mice in vivo. The analysis of SARC-L1 tumor microenvironment revealed a strong infiltration by T cells expressing inhibitory receptors such as PD-1 and TIM-3. Finally, we found that SARC-L1 is sensitive to several drugs commonly used to treat sarcoma and also susceptible to anti-PD-L1 monoclonal antibody therapy in vivo. Collectively, we described a novel syngeneic tumor model A2/DR1 mice that could be used as preclinical tool for the evaluation of antitumor immunotherapies.

Published
2017
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17. CIITA-transduced glioblastoma cells uncover a rich repertoire of clinically relevant tumor-associated HLA-II antigens

Author

Michal Bassani-Sternberg, Elise Ramia, Brian Stevenson, Greta Forlani, Elodie Lauret Marie Joseph, Michael Linnebacher, Roberto S. Accolla, Florian Huber, HuiSong Pak, and Justine Michaux

Subjects
Antigen discovery, CIITA, Cancer Biology, Cancer therapeutics, Glioblastoma, HLA class II, Immunology, Immunopeptidomics, Mass Spectrometry, Tumor antigens, HLA-II, human leukocyte antigen class II, Biochemistry, Epitope, WES, whole-exome sequencing, Analytical Chemistry, APCs, antigen presenting cells, 0303 health sciences, biology, Brain Neoplasms, 030302 biochemistry & molecular biology, a.u., arbitrary units, Nuclear Proteins, TH, T helper cells, 3. Good health, TAAs, tumor-associated antigens, medicine.anatomical_structure, SNPs, single nucleotide polymorphisms, PSM, peptide spectrum match, HLA-I, human leukocyte antigen class I, FDR, false discovery rate, T cell, Class II major histocompatibility complex transactivator, Human leukocyte antigen, Major histocompatibility complex, TcR, T cell receptors, IFNγ, Interferon gamma, ER, endoplasmic reticulum, 03 medical and health sciences, Antigen, Special Issue: Immunopeptidomics, ERAAP, ER aminopeptidase-associated with antigen processing, Antigens, Neoplasm, Cell Line, Tumor, medicine, MHC, major histocompatibility complex, Animals, Humans, Antigen-presenting cell, Molecular Biology, 030304 developmental biology, PBMCs, peripheral blood mononuclear cells, HLA, human leukocyte antigen, Research, T-cell receptor, Histocompatibility Antigens Class II, LFQ, label-free quantification, TAP, transporter-associated with antigen processing, CTL, cytotoxic T cells, CIITA, class II major histocompatibility complex transactivator, HCD, higher-energy collision dissociation, biology.protein, Cancer research, Trans-Activators, Antigens, Neoplasm/immunology, Brain Neoplasms/immunology, Cattle, Glioblastoma/immunology, Histocompatibility Antigens Class II/immunology, Nuclear Proteins/genetics, Nuclear Proteins/immunology, Peptides/immunology, Trans-Activators/genetics, Trans-Activators/immunology, GBM, glioblastoma, Peptides, SNVs, single nucleotide variants
Abstract

CD4+ T cell responses are crucial for inducing and maintaining effective anticancer immunity, and the identification of human leukocyte antigen class II (HLA-II) cancer-specific epitopes is key to the development of potent cancer immunotherapies. In many tumor types, and especially in glioblastoma (GBM), HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in GBM. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed and sensitive mass spectrometry–based immunopeptidomics analysis, we here uncovered a remarkable breadth of the HLA-ligandome in HROG02, HROG17, and RA GBM cell lines. The effect of CIITA expression on the induction of the HLA-II presentation machinery was striking in each of the three cell lines, and it was significantly higher compared with interferon gamma (IFNɣ) treatment. In total, we identified 16,123 unique HLA-I peptides and 32,690 unique HLA-II peptides. In order to genuinely define the identified peptides as true HLA ligands, we carefully characterized their association with the different HLA allotypes. In addition, we identified 138 and 279 HLA-I and HLA-II ligands, respectively, most of which are novel in GBM, derived from known GBM-associated tumor antigens that have been used as source proteins for a variety of GBM vaccines. Our data further indicate that CIITA-expressing GBM cells acquired an antigen presenting cell-like phenotype as we found that they directly present external proteins as HLA-II ligands. Not only that CIITA-expressing GBM cells are attractive models for antigen discovery endeavors, but also such engineered cells have great therapeutic potential through massive presentation of a diverse antigenic repertoire., Graphical Abstract, Highlights • CIITA-expressing glioblastoma cells express high levels of HLA-II complexes. • CIITA induces peptide presentation across the HLA-DP, -DQ, and -DR allotypes. • Many clinically relevant glioblastoma-associated tumor antigens were detected. • Such cells may have great therapeutic potential in clinical settings., In Brief CD4+ T cell responses are crucial for inducing and maintaining effective anticancer immunity; however, in glioblastoma and many solid tumors, HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in glioblastoma. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed immunopeptidomics, we uncovered a remarkable breadth of the HLA-ligandome in three glioblastoma cell lines and identified many cancer-associated ligands with implications for the development of cancer immunotherapies.

Published
2020

18. Immunoregulation and Clinical Implications of ANGPT2/TIE2

Author

Elodie, Lauret Marie Joseph, Caroline, Laheurte, Marine, Jary, Laura, Boullerot, Kamal, Asgarov, Eléonore, Gravelin, Adeline, Bouard, Laurie, Rangan, Magalie, Dosset, Christophe, Borg, and Olivier, Adotévi

Subjects
Aged, 80 and over, Male, Lung Neoplasms, Myeloid-Derived Suppressor Cells, T-Lymphocytes, Middle Aged, Prognosis, Receptor, TIE-2, Angiopoietin-2, Survival Rate, Carcinoma, Non-Small-Cell Lung, Biomarkers, Tumor, Immune Tolerance, Humans, Female, Tumor Escape, Aged, Neoplasm Staging
Abstract

Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non-small cell lung cancer (NSCLC). Greater numbers of circulating TIE2

Published
2019

19. Circulating NKp46+ Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer

Author

Elodie Lauret Marie Joseph, Laura Boullerot, Françoise Le Pimpec-Barthes, Caroline Laheurte, Emilie Picard, Olivier Adotevi, Laurent Beziaud, Magalie Dosset, Jeanne Galaine, Christophe Borg, Virginie Westeel, Marion Jacquin, Béatrice Gaugler, Elizabeth Fabre, Romain Loyon, Laurie Spehner, Yann Godet, Guillaume Eberst, and Anne Caignard

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Immunology, Biology, CD16, lcsh:RC254-282, cd16, 03 medical and health sciences, nsclc, nkp46, 0302 clinical medicine, medicine, Immunology and Allergy, Cytotoxic T cell, Cytotoxicity, Receptor, Lung cancer, nk cells, Degranulation, Cancer, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosurveillance, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, prognosis, lcsh:RC581-607
Abstract

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56dim CD16+ NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56bright NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56dim CD16− phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56dim CD16− NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46+ NK cell subsets was absent in HD. We showed that the rate of circulating NKp46+ CD56dim CD16+ NK cells influenced the patients’ survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46+ NK cell subset in NSCLC patients.

Published
2019

20. Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy

Author

Laurent, Beziaud, Laura, Boullerot, Thi, Tran, Laura, Mansi, Elodie Lauret, Marie-Joseph, Patrice, Ravel, Ludger, Johannes, Jagadeesh, Bayry, Eric, Tartour, Olivier, Adotévi, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
CD4-Positive T-Lymphocytes, Sirolimus, Mice, Inbred BALB C, Receptors, CCR4, Vaccination, Antineoplastic Agents, CD8 T cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Cancer Vaccines, rapalog, regulatory CD4 T cells, Mice, Inbred C57BL, Mice, CCR4 antagonist, Cell Line, Tumor, Animals, Female, cancer vaccine, Immunologic Memory, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cell Proliferation
Abstract

International audience; mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127+ CD62L+ ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (Tregs ) expansion in vivo limits the efficacy of the bi-therapy by altering the antitumor CD8 T-cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent Tregs induction considerably improved the efficacy of the bi-therapy by enhancing CD8 T cells-mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit Tregs .

Published
2018
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21. Circulating NKp46

Author

Emilie, Picard, Yann, Godet, Caroline, Laheurte, Magalie, Dosset, Jeanne, Galaine, Laurent, Beziaud, Romain, Loyon, Laura, Boullerot, Elodie, Lauret Marie Joseph, Laurie, Spehner, Marion, Jacquin, Guillaume, Eberst, Béatrice, Gaugler, Françoise, Le Pimpec-Barthes, Elizabeth, Fabre, Virginie, Westeel, Anne, Caignard, Christophe, Borg, and Olivier, Adotévi

Subjects
Original Research
Abstract

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56(dim) CD16(+) NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56(bright) NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56(dim) CD16(−) phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56(dim) CD16(−) NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46(+) NK cell subsets was absent in HD. We showed that the rate of circulating NKp46(+) CD56(dim) CD16(+) NK cells influenced the patients’ survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46(+) NK cell subset in NSCLC patients.

Published
2018

22. Abstract 575: Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer

Author

Caroline Laheurte, Elodie Lauret Marie Joseph, Magalie Dosset, Olivier Adotevi, Laurie Cuche, Dewi Vernerey, Marion Jacquin, Laura Boullerot, Virginie Westeel, P. Jacoulet, Vincent Kaulec, and Guillaume Eberst

Subjects
Cancer Research, Telomerase, business.industry, ELISPOT, T cell, Cancer, Human leukocyte antigen, medicine.disease, Immune system, medicine.anatomical_structure, Oncology, Cancer research, medicine, Cytotoxic T cell, business, Lung cancer
Abstract

Despite the critical roles played by IFN-γ+ CD4 Th1 response in tumor immunity, the translation of their potential in clinic remains challenging. Here, we evaluate the clinical significance of circulating anti-tumor CD4 Th1 response in non-small cell lung cancer (NSCLC) patients. 170 naïve-treatment patients were enrolled in this immune monitoring study. The antitumor adaptive Th1 response was assessed by IFN-γ ELISPOT assay in blood lymphocytes using a mixture of eight highly promiscuous and Th1-polarized HLA class II-restricted epitopes from telomerase (TERT). The presence of anti-TERT Th1 response was detected in 59/170 patients (35%). We found an opposite link between anti-TERT Th1 and hyper exhausted T cells co-expressing PD-1+ and TIM-3+ in NSCLC patients. In contrast to hyper exhausted CD8 T cells, the presence of anti-TERT Th1 response was associated with a low rate of hyper exhausted CD4 T cells. We showed that NSCLC stage dissemination is associated with a decrease of anti-TERT Th1 response but an increase of circulating hyper exhausted PD-1+/TIM-3+ CD4 T cells. Notably, anti-telomerase Th1 response and hyper exhausted CD4 T-cells displayed opposite prognosis value in NSCLC. While high level of anti-TERT Th1 cells play a protective role, hyper-exhausted PD-1+TIM-3+ CD4 T cells negatively affect patients’ survival. By using these two circulating immune factors, we stratified patients in distinct prognostic group. Patients with anti-TERT Th1high/CD4 PD-1 TIM-3low immune profile had better overall survival than anti-TERT Th1low/CD4 PD-1 TIM-3high group (median OS : not reached versus 4 months respectively p Citation Format: Caroline Laheurte, Magalie Dosset, Dewi Vernerey, Elodie Lauret Marie Joseph, Laura Boullerot, Vincent Kaulec, Marion Jacquin, Laurie Cuche, Guillaume Eberst, Pascale Jacoulet, Virginie Westeel, Olivier Adotevi. Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 575.

Published
2019
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23. Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity

Author

Lise Queiroz, Francis Bonnefoy, Béatrice Gaugler, Clémentine Gamonet, Sindy Vrecko, Olivier Adotevi, Eric Tartour, Antoine Thiery-Vuillemin, Thierry Nguyen Tan Hon, Jean-René Pallandre, Laura Mansi, Christophe Borg, Guillaume Mouillet, Patrice Ravel, Elsa Curtit, Yann Godet, Tristan Maurina, Jagadeesh Bayry, Caroline Laheurte, Elodie Lauret Marie-Joseph, Laura Boullerot, Bernard Royer, Xavier Pivot, Laurent Beziaud, L. Rangan, Herrada, Anthony, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])

Subjects
0301 basic medicine, Cancer Research, T-Lymphocytes, CCR4, Pharmacology, Mice, 0302 clinical medicine, MESH: Animals, Telomerase, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, TOR Serine-Threonine Kinases, FOXP3, MESH: Telomerase, MESH: Carcinoma, Renal Cell, Kidney Neoplasms, Temsirolimus, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Female, MESH: Immunosuppressive Agents, Immunosuppressive Agents, medicine.drug, MESH: Cell Line, Tumor, MESH: Interferon-gamma, MESH: Mice, Inbred BALB C, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Everolimus, Interferon-gamma, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, MESH: Mice, Inbred C57BL, Cell Line, Tumor, medicine, Animals, Humans, Everolimus, Carcinoma, Renal Cell, MESH: Mice, PI3K/AKT/mTOR pathway, MESH: TOR Serine-Threonine Kinases, MESH: Humans, Cancer, MESH: Interleukin-2, Th1 Cells, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, MESH: T-Lymphocytes, MESH: Th1 Cells, Interleukin-2, MESH: Kidney Neoplasms, MESH: Female, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes+CD8+ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100–12. ©2016 AACR.

Published
2016
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24. Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors

Author

Magalie Dosset, Elodie Lauret-Marie Joseph, Thaiz Rivera Vargas, and Lionel Apetoh

Subjects
T cells, Review, chemotherapy, Combined Modality Therapy, Models, Biological, immunogenic therapy, immune checkpoint inhibitors, lcsh:Biology (General), Neoplasms, vaccine, Animals, Humans, cancer, resident-memory T cells, Immunotherapy, lcsh:QH301-705.5, Immunologic Memory, combined therapies, radiotherapy, stem-cell like memory T cells
Abstract

Immune checkpoint inhibitors (ICPi) have shown their superiority over conventional therapies to treat some cancers. ICPi are effective against immunogenic tumors. However, patients with tumors poorly infiltrated with immune cells do not respond to ICPi. Combining ICPi with other anticancer therapies such as chemotherapy, radiation, or vaccines, which can stimulate the immune system and recruit antitumor T cells into the tumor bed, may be a relevant strategy to increase the proportion of responding patients. Such an approach still raises the following questions: What are the immunological features modulated by immunogenic therapies that can be critical to ensure not only immediate but also long-lasting tumor protection? How must the combined treatments be administered to the patients to harness their full potential while limiting adverse immunological events? Here, we address these points by reviewing how immunogenic anticancer therapies can provide novel therapeutic opportunities upon combination with ICPi. We discuss their ability to create a permissive tumor microenvironment through the generation of inflamed tumors and stimulation of memory T cells such as resident (TRM) and stem-cell like (TSCM) cells. We eventually underscore the importance of sequence, dose, and duration of the combined anticancer therapies to design optimal and successful cancer immunotherapy strategies.

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25. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer

Author

Magalie Dosset, Thaiz Rivera Vargas, Anaïs Lagrange, Romain Boidot, Frédérique Végran, Aurélie Roussey, Fanny Chalmin, Lucile Dondaine, Catherine Paul, Elodie Lauret Marie-Joseph, François Martin, Bernhard Ryffel, Christophe Borg, Olivier Adotévi, François Ghiringhelli, and Lionel Apetoh

Subjects
chemotherapy, colorectal cancer, adaptive immune resistance, pd-1/pd-l1 pathway, immunotherapy, cd8 t cells, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Chemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1+ CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-γ secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.

Published
2018
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