Abstract
Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection. Vaccination elicited an early rise of CD11b+ myeloid cells that preceded and conditioned the intra-tumoral accumulation of CD8+ T cells. Conversely, CD8+ T cells and IFNγ production activated myeloid cells were required for tumor regression. A 4-fold reduction of CD8+ T cell infiltrate in CXCR3KO mice did not prevent tumor regression, whereas a reduction of tumor-infiltrating myeloid cells significantly interfered with vaccine efficiency. We show that macrophages from regressing tumors can kill tumor cells in two ways: phagocytosis and TNFα release. Altogether, our data suggest new strategies to improve the efficiency of cancer immunotherapies, by promoting intra-tumoral cooperation between macrophages and T cells.
Highlights
T lymphocytes play an important role in restraining tumor development
CSF-1 overexpression and high densities of intratumoral macrophages are often considered as indicators of poor prognosis for cancer patients [21, 22]
Even if this is true in progressing tumors, this should not hide the fact that appropriately stimulated macrophages may directly or indirectly slow down tumor growth [23, 24]
Summary
T lymphocytes play an important role in restraining tumor development. Their infiltration in most human primary tumors is associated with better prognosis [1]and they seem to keep in check disseminated tumor cells and metastatic outgrowth [2]. T lymphocytes play an important role in restraining tumor development. Their infiltration in most human primary tumors is associated with better prognosis [1]. They seem to keep in check disseminated tumor cells and metastatic outgrowth [2] Based on these notions, various types of T-cell based immunotherapies have been developed for treating cancer patients, and provided encouraging clinical results in the past few years. The immune system has been shaped by evolution so as to fight infections, not cancer, and efficient immune responses against viruses or bacteria invariably require a whole set of cellular interactions. When these pathogens are cleared, the immune responses are transient, with an acute and a recovery phase that are quite different, and both necessary for the efficacy and the safety of the system [6]
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