Final Report Summary - T CELL HOMEOSTASIS (Conditioning regimens shape the homeostasis of adoptively transferred T cells: Effects on autoreactivity and role in anti-tumor therapy)
Executive Summary:
Many advances in cancer therapy have been achieved during the past decade but metastatic cancers remain extremely difficult to treat. As a result, new strategies are being developed with one focus aimed at harnessing the immune system to target and eradicate tumors. Adoptive T cell immunotherapy involves the transfer of tumor-specific T cells that have been manipulated and expanded ex vivo. While immunotherapy strategies have demonstrated their potential, optimizing the persistence and responsiveness of adoptively transferred T cells remains a significant challenge. As lymphopenia itself results in the differentiation and activation of the T cell compartment, the induction of this state has been exploited to enhance the anti-tumor efficacy of adoptively transferred T cells. However, we have only little knowledge as to whether different lymphopenia-inducing regimens are equal in their capacity to “support” T cell expansion and differentiation to T effector fates. Here, we show that the fate of T cell populations is strikingly changed by adoptive transfer into mice rendered lymphopenic by sub-lethal irradiation as compared to a busulphan/cyclophosphamide (Bu/Cy) chemotherapy regimen. Irradiation-mediated lymphopenia resulted in a skewed proliferation of donor CD8+ T cells whereas Bu/Cy treatment induced a massive IL-7-independent proliferation of donor CD4+ T cells. Notably, this latter proliferation was associated with a significant expansion of adoptively transferred Foxp3+ suppressive T cells in Bu/Cy-treated mice. As the level of lymphopenia induced by chemotherapy and irradiation was very similar, our data strongly suggest that conditioning-triggered changes in the host environment, rather than lymphopenia per se, modulate the fate of adoptively transferred T cells. Indeed, our data show that the numbers as well as subsets of dendritic cells (DCs) differ in irradiated and Bu/Cy-treated mice. Furthermore, we observed a very different spatial organization of the lymphoid tissues in the 2 different lymphopenic environments and important variations in cytokine availability. Moreover, efficient depletion of host DC significantly attenuated the fast proliferation of adoptively-transferred CD4+ T cells in Bu/Cy-treated mice. Thus, lymphopenia-inducing regimens are not equivalent and our data demonstrate that their distinct effects on host DC subsets regulate the proliferation and function of adoptively-transferred T cells. An understanding of these parameters will be crucial for the future development of immunotherapy protocols.