ORCID Profile
0000-0003-3511-3219
Current Organisation
Centre De Recherche contre le Cancer de Toulouse - Oncopôle
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Publisher: Wiley
Date: 14-02-2019
DOI: 10.1002/IJC.32120
Publisher: MDPI AG
Date: 02-07-2020
Abstract: In the past 20 years, the immune system has increasingly been recognized as a major player in tumor cell control, leading to considerable advances in cancer treatment. While promising with regards to melanoma, renal cancer and non-small cell lung cancer, immunotherapy provides, for the time being, limited success in other cancers, including ovarian cancer, potentially due to insufficient immunogenicity or to a particularly immunosuppressive microenvironment. In this review, we provide a global description of the immune context of ovarian cancer, in particular epithelial ovarian cancer (EOC). We describe the adaptive and innate components involved in the EOC immune response, including infiltrating tumor-specific T lymphocytes, B lymphocytes, and natural killer and myeloid cells. In addition, we highlight the rationale behind the use of EOC preclinical mouse models to assess resistance to immunotherapy, and we summarize the main preclinical studies that yielded anti-EOC immunotherapeutic strategies. Finally, we focus on major published or ongoing immunotherapy clinical trials concerning EOC.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2014
DOI: 10.1007/S00262-014-1581-4
Abstract: Forkhead box P3 (Foxp3) is an important transcription factor that belongs to the forkhead/winged-helix family of transcriptional regulators. Foxp3 has been extensively studied over the past 13 years as a master regulator of transcription in a specific T-cell type, CD4(+) regulatory T cells (Treg), both in humans and in mice. Compelling data characterize Foxp3 as critically important and necessary for the development and the differentiation of Treg. It has been considered initially as the only specific marker for Treg. However, recent work has proposed that Foxp3 can be expressed by other types of lymphoid cells or myeloid cells and also by some non-hematopoietic cells such as epithelial cells. It remains controversial about the expression of Foxp3 in cells other than Treg, but understanding the potential expression and function of this master regulator in different cell subsets could have a wide range of implications for immune tolerance and several pathologies including autoimmune disorders and immune responses to cancer.
Publisher: Informa UK Limited
Date: 09-2013
DOI: 10.4161/ONCI.25962
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-06-2023
DOI: 10.1126/SCIIMMUNOL.ADG8841
Abstract: Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here, we show, in metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic α4β7 integrin–expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti–PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of α4β7 + cells abrogated control of metastases. Last, in patients with metastatic CRC, response to ICB was associated with expression of α4β7 integrin in metastases and with circulating α4β7 + CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor-specific α4β7 + CD8 T cells.
Publisher: Informa UK Limited
Date: 08-2013
DOI: 10.4161/ONCI.25961
Publisher: Informa UK Limited
Date: 2021
Publisher: American Association for Cancer Research (AACR)
Date: 14-10-2013
DOI: 10.1158/1078-0432.CCR-13-0458
Abstract: Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression. Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2+ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach. Results: In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8+ T cells following antigen-specific stimulation with PD-L1+ tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2+ tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1+ CD11b+ myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. Conclusion: This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer. Clin Cancer Res 19(20) 5636–46. ©2013 AACR.
Publisher: Public Library of Science (PLoS)
Date: 29-09-2014
Publisher: Informa UK Limited
Date: 2020
Publisher: Public Library of Science (PLoS)
Date: 09-01-2013
Publisher: MDPI AG
Date: 28-07-2022
Abstract: Tumor-infiltrating exhausted PD-1hiCD39+ tumor-antigen (Ag)-specific CD4 T cells contribute to the response to immune checkpoint blockade (ICB), but their circulating counterparts, which could represent accessible biomarkers, have not been assessed. Here, we analyzed circulating PD-1+CD39+ CD4 T cells and show that this population was present at higher proportions in cancer patients than in healthy in iduals and was enriched in activated HLA-DR+ and ICOS+ and proliferating KI67+ cells, indicative of their involvement in ongoing immune responses. Among memory CD4 T cells, this population contained the lowest proportions of cells producing effector cytokines, suggesting they were exhausted. In patients with HPV-induced malignancies, the PD-1+CD39+ population contained high proportions of HPV Ag-specific T cells. In patients treated by ICB for HPV-induced tumors, the proportion of circulating PD-1+CD39+ CD4 T cells was predictive of the clinical response. Our results identify CD39 expression as a surrogate marker of circulating helper tumor-Ag-specific CD4 T cells.
Publisher: Public Library of Science (PLoS)
Date: 07-05-2013
Publisher: Springer Science and Business Media LLC
Date: 16-02-2011
Publisher: American Association for Cancer Research (AACR)
Date: 07-2020
DOI: 10.1158/2326-6066.CIR-19-0855
Abstract: Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
Publisher: Informa UK Limited
Date: 02-11-2014
Publisher: Wiley
Date: 17-01-2017
DOI: 10.1038/ICB.2016.128
Abstract: The potential for immunotherapy as a treatment option for cancer is clear from remarkable responses of some leukemia patients to adoptive cell transfer using autologous T cells genetically modified to express chimeric antigen receptors (CARs). However, the vast majority of cancers, in particular the more common solid cancers, such as those of the breast, colon and lung, fail to respond significantly to infusions of CAR T cells. Solid cancers present some formidable barriers to adoptive cell transfer, including suppression of T-cell function and inhibition of T-cell localization. In this review, we discuss the current state of CAR T-cell therapy in solid cancers, the variety of concepts being investigated to overcome these barriers as well as approaches aimed at increasing the specificity and safety of adoptive cell transfer.
Publisher: American Society for Clinical Investigation
Date: 25-01-2021
Publisher: Springer Science and Business Media LLC
Date: 26-04-2013
DOI: 10.1007/S00262-013-1402-1
Abstract: The role of human intraepithelial Vδ1(+) γδ T cell cytotoxic effectors in the immune surveillance against metastatic colon cancer has never been addressed, despite their reported capacity to infiltrate colon carcinomas and to kill colonic cancer cells in vitro. We previously showed that Vδ1(+) γδ T cells are enriched in blood in response to cytomegalovirus (CMV) infection, and that such increase may be protective against epithelial cancers. The objective of the present study was to investigate whether CMV-induced Vδ1(+) γδ T lymphocytes could inhibit the propagation of human colon tumors in vivo, in order to evaluate their immunotherapeutic potential in this context. Even though metastases are an important cause of death in various cancers including colorectal cancer (CRC), the anti-metastatic effect of immune effectors has been poorly analyzed. To this purpose, we set up a reliable model of metastatic colon cancer through orthotopic implantation of luciferase-expressing human HT29 cells in immunodeficient mice. Using bioluminescence imaging to follow the outcome of colonic cancer cells, we showed that a systemic treatment with CMV-induced Vδ1(+) γδ T cells could not only inhibit primary colon tumor growth but also the emergence of secondary tumor foci in the lungs and liver. Finally, our data lead to propose that Vδ1(+) γδ T lymphocytes may directly influence the appearance of metastases independently from their control of primary tumor size. These findings, which extend our previous work, pave the road for the potential manipulation of Vδ1(+) γδ T lymphocytes in novel anti-CRC immunotherapeutic protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2009
DOI: 10.1158/0008-5472.CAN-08-3037
Abstract: γδ T cells recognize stress-induced autoantigens and contribute to immunity against infections and cancer. Our previous study revealed that Vδ2-negative (neg) γδ T lymphocytes isolated from transplant recipients infected by cytomegalovirus (CMV) killed both CMV-infected cells and HT29 colon cancer cells in vitro. To investigate the antitumor effects of Vδ2neg clones in vivo, we generated hypodermal HT29 tumors in immunodeficient mice. Concomitant injections of Vδ2negclones, in contrast to Vδ2+ cells, prevented the development of HT29 tumors. Vδ2neg clones expressed chemokine C-C motif receptor 3 (CCR3) and migrated in vitro in response to chemokines secreted by HT29 cells, among which were the CCR3 ligands macrophage inflammatory protein-1δ and monocyte chemoattractant protein-4. More importantly, a systemic i.p. treatment with Vδ2neg clones delayed the growth of HT29 s.c. tumors. The effect of in vivo γδ T-cell passive immunotherapy on tumor growth could be reverted by addition of a blocking anti-CCR3 antibody. γδ T-cell passive immunotherapy was dependent on the cytotoxic activity of the γδ effectors toward their targets because Vδ2neg clones were not able to inhibit the growth of A431 hypodermal tumors. Our findings suggest that CMV-specific Vδ2neg cells could target in vivo cancer cells, making them an attractive candidate for antitumor immunotherapy. [Cancer Res 2009 (9):3971–8]
Publisher: Proceedings of the National Academy of Sciences
Date: 20-08-2013
Abstract: CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A 2A /A 2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A 2A −/− mice were strongly protected against tumor metastasis, indicating that host A 2A receptors enhanced tumor metastasis. A 2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A 2A blockade was due to enhanced NK cell function. Interestingly, A 2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73 + tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A 2A or A 2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A 2A /A 2B receptor antagonists have already entered clinical trials in other therapeutic settings.
Publisher: Public Library of Science (PLoS)
Date: 27-10-2015
Publisher: Future Medicine Ltd
Date: 06-2013
DOI: 10.2217/IMT.13.37
Abstract: Aim: The aim of the current study was to fully elucidate the functions of T cells genetically modified with an erbB2-specific chimeric antigen receptor (CAR). Material & methods: In this study, key functional parameters of CAR T cells were examined following antigen-specific stimulation of the chimeric anti-erbB2 receptor. Results: Gene-modified T cells produced the cytokines IFN-γ, IL-2, IL-4, IL-10, TNF-α and IL-17, and the chemokine RANTES upon CAR ligation. A multifunctional capacity of these CAR T cells was also demonstrated, where 13.7% of cells were found to simultaneously express IFN-γ and CD107a, indicative of cytolytic granule release. In addition, the CAR T cells were able to respond to a greater degree on the second ligation of CAR, which has not been previously shown. IFN-γ secretion levels were significantly higher on second ligation than those secreted following initial ligation. CAR-expressing T cells were also demonstrated to lyze erbB2-expressing tumor cells in the absence of activity against bystander cells not expressing the erbB2 antigen, thereby demonstrating exquisite specificity. Conclusion: This study demonstrates the specificity of CAR gene-engineered T cells and their capacity to deliver a wide range of functions against tumor cells with an enhanced response capability after initial receptor engagement.
Publisher: Impact Journals, LLC
Date: 03-05-2016
Location: France
No related grants have been discovered for christel DEVAUD.