Il est maintenant bien établi que le système immunitaire joue un rôle majeur dans le contrôle des tumeurs, y compris dans les carcinomes pulmonaires. Cependant, les interactions entre les cellules tumorales et les cellules immunitaires du microenvironnement tumoral sont mal connues. Dans ce travail, nous avons étudié les caractéristiques morphologiques et moléculaires des cellules tumorales provenant d’adénocarcinomes pulmonaires et leur association avec la composition du microenvironnement immunitaire. Nous avons rapporté la valeur pronostique des paramètres morphologiques de ces tumeurs, comme le grade histologique des adénocarcinomes, et leur association avec le statut moléculaire EGFR et KRAS. Nous avons émis l’hypothèse que la diversité morphologique et moléculaire de ces tumeurs pouvait être associée à une signature immunitaire intra-tumorale spécifique et que cela pourrait avoir un impact pronostique. Nous avons mis en évidence que la densité des cellules dendritiques matures, situées au sein de structures lymphoïdes tertiaires, variait en fonction du statut moléculaire EGFR et KRAS des tumeurs. De même, l’impact pronostique des cellules dendritiques matures et des lymphocytes CD8+ variait en fonction du statut moléculaire des tumeurs. Nous avons également retrouvé la valeur pronostique de l’environnement immunitaire, représenté par la densité en cellules dendritiques matures et en lymphocytes CD8+, sur la survie à long terme des carcinomes pulmonaires de stade III-N2 opérés après chimiothérapie néoadjuvante. Enfin, nous avons démontré que la chimiothérapie n'est pas associée à de profondes modifications de l’infiltrat immunitaire, alors qu’elle entraîne des modifications des cellules tumorales. L’ensemble de ces résultats suggère que l’infiltrat immunitaire est intimement lié à la cellule tumorale et que la composition du microenvironnement immunitaire varie avec les caractéristiques de la tumeur. Cette interaction entre les cellules tumorales et les cellules immunitaires contribue au pronostic de ces tumeurs. Ces données démontrent l’intérêt d’utiliser des traitements combinant des drogues cytotoxiques, telle la chimiothérapie conventionnelle, à des traitements immunomodulateurs permettant de favoriser une réponse immunitaire anti-tumorale efficace. / The major role of the immune system against tumor development is now clearly established, including lung carcinoma. Nevertheless, interaction between tumoral cells and immune environment is less well-defined. In that study, we have studied morphological and molecular tumoral cells characteristics from lung adenocarcinoma and their role in the composition of immune environment. We reported the prognostic value of morphological parameters, as histological grade of adenocarcinoma, and their association with molecular EGFR and KRAS status. We hypothesized that morphological and molecular diversity of these tumors could be associated with a specific intratumoral immune signature, and could have an impact in prognosis. We showed that mature dendritic cells density, located in tertiary lymphoid structures, differed according to EGFR and KRAS status. Morever, molecular status of tumors modified the pronostic value of mature dendritics cells and CD8+ T cells. We found a prognostic value of immune environment, represented by dendritic cells and T CD8+ cells, in operated stage III-N2 lung carcinomas treated by neoadjuvant chemotherapy. At last, we demonstrated that chemotherapy is not associated with wide modifications in immune infiltrate, whereas it induced modifications in tumoral cells. All together, these data strongly argue for a close link between tumoral cells and immune environment, which seems to depend on tumoral cell characteristics. This interaction between tumoral cells and immune cells contribute to the prognosis of these tumors. These results show the evidence that combine cytotoxic treatment, like conventional chemotherapy, with immunomodulators, favour a protective anti-tumor immune response.

Indiana University-Purdue University Indianapolis (IUPUI) / Immunotherapy for cancer has held much promise as a potent modality of cancer treatment. The ability to selectively destroy diseased cells and leave healthy cells unharmed has been the goal of cancer immunotherapy for the past thirty years. However, the full capabilities of cancer immunotherapies have been elusive. Cancer immunotherapies have been consistently hampered by limited immune reactivity, a diminishing immune response over time, and a failure to overcome self-tolerance. Many of these deficiencies have been borne-out by immunotherapies that have focused on the adoptive transfer of activated or genetically modified mature CD8+ T cells. The limitations inherent in therapies involving terminally differentiated mature lymphocytes include limited duration, lack of involvement of other components of the immune system, and limited clinical efficacy. We sought to overcome these limitations by altering and enhancing long-term host immunity by genetically modifying then transplanting HSCs. To study these questions and test the efficiency of gene transfer, we cloned a tumor reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen TRP-1, then constructed both a high expression lentiviral delivery system and a TCR Tg expressing the same TCR genes. We demonstrate with both mouse and human HSCs durable, high-efficiency TCR gene transfer, following long-term transplantation. We demonstrate the induction of spontaneous autoimmune vitiligo and a TCR-specific TH1 polarized memory effector CD4+ T cell population. Most importantly, we demonstrate the destruction of subcutaneous melanoma without the aid of vaccination, immune modulation, or cytokine administration. Overall, these results demonstrate the creation of a novel translational model of durable lentiviral gene transfer, the induction of spontaneous CD4+ T cell immunity, the breaking of self-tolerance, and the induction of anti-tumor immunity.