Revisiting the role of T cells in tumor regression

Abstract

It is now clear that solid tumors can be infiltrated by immune cells able to play both proand anti-tumoral roles. Based on the fact that in most (though not all) human cancers, a good prognosis is associated with the presence of tumorinfiltrating lymphocytes (TIL), the current model places T cells as central actors of the antitumor immune action, i.e., they are expected to directly kill tumor cells, and to be the main final effectors of tumor cell death (Fig. 1, left). A frequently overlooked paradox is that TIL present in primary tumors cannot be the ones that will attack tumors in patients after resection of their primary tumor; at most, they are indicative of an ongoing T cell response, hopefully with clones persisting in patients after resection, with a role in immune surveillance (an issue distinct from tumor regression) and a better outcome. In many murine tumor models, tumor growth is accelerated when animals are depleted of circulating T cells (almost always CD8). The importance of perforin in this issue remains controversial. The fact that tumors grow despite the presence of TIL is generally explained by the fact that TIL become unresponsive in an immunosuppressive microenvironment and thus, cannot do their job to attack tumor cells. Another frequent argument in favor of a direct cytotoxic effect of anti-tumoral T cells is the therapeutic success of adoptive transfer of anti-tumor T lymphocytes in some human cancers. In these trials, the existence of interactions between transferred T cells and tumor cells has been illustrated but such interactions have never been quantified. However, in a murine model of adoptive transfer of T cells, it has been shown that when tumors melt, the vast majority of transferred T cells accumulated at the periphery of the tumor, the tumor nest being mainly invaded by Gr1 innate cells (neutrophils and/or inflammatory monocytes). In addition, the slow rate at which cytotoxic T cells can kill tumor cells in situ is hardly compatible with the idea that such an effect may be efficient against rapidly dividing tumor cells. Conversely, innate cells like NK, cdT cells and macrophages act rapidly to kill and/or phagocyte. In addition, efficacy of monoclonal antibodies in cancer therapy is strongly associated with Fc receptordependent mechanisms and cell-mediated cytotoxicity which are properties shared by these potent innate effectors. Thus, all these observations do not fit well with the current model of TIL killing directly tumor cells and of cytotoxic T cells being the main final effectors against tumor cells. Despite this, the current model is largely prevailing, with major consequences. Indeed, even if other concepts are taken into account, such as the importance of limiting immunosuppression, or making the appropriate combinations of chemoand immunotherapy, most clinical trials of active immunotherapy still aim at generating highly reactive T cells as the main way to optimize a tumor attack. We consider that this point of view needs to be revisited. OncoImmunology 1:3, 346–350; May/June 2012; G 2012 Landes Bioscience

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Cite this paper

@inproceedings{Bercovici2012RevisitingTR, title={Revisiting the role of T cells in tumor regression}, author={Nad{\`e}ge Bercovici and Alain Trautmann}, year={2012} }