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Immunothérapie du cancer [Cancer immunotherapy]

voir version anglaise [There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of our study is to better understand how the host immune system is involved in the success of chemotherapy. We use the P815 mastocytoma of DBA/2 mice, as this tumor is poorly immunogenic, expresses well defined antigens and can elicit the differentiation of T cells specific to tumor-associated and/or tumor-specific antigens in some conditions. We have shown recently that treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long-term protection in a CD4- and CD8-dependent manner. A population of inflammatory-type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4-dependent infiltration, in tumor bed, of tumor-specific CD8+ T lymphocytes. Our data point to a major role of CD4+ T cells in inducing chemokine expression in the tumor, provoking migration of tumor-specific CXCR3+ CD8+ T lymphocytes.Importantly, the analysis of CD8+ T cells specific to P1A/H-2Ld and P1E/H-2Kd revealed that cyclophosphamide altered the P815-specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen. This question is of major importance for immunotherapy to define the role of tumor-associated (encoded by cancer-germline gene) versus tumor-specific (encoded by a mutated gene) antigens as tumor rejection antigens.Collectively our observation reinforce the concept that chemotherapy relies on the immune response to achieve full remission in an experimental tumor model and suggest that that in some instances, chemotherapy may achieve long term effects by favoring the establishment of an immune, memory-like anti-tumor response. Future experiments will attempts to better understand the mechanism whereby chemotherapeutic agents such as cyclophosphamide allow the establishment of an effective immune response to tumor antigens. ]



disciplines et mots clés déclarés

Biologie cellulaire

cancer immunothérapie