Chimeric antigen receptor (CAR) T cell cytokines shape myeloid cell function within the tumor microenvironment and activate host lymphocytes for tumor elimination. (165.4)

Abstract

Abstract The infiltration of suppressive myeloid cells into the tumor microenvironment restrains anti-tumor immunity. However, T cell effector cytokines can shape the function of the myeloid lineage to support tumor rejection, regulating the balance between pro- and anti-tumor immunity. In this study, it is shown that effector cytokines secreted by adoptively transferred T cells expressing a chimeric antigen receptor (CAR) shape the function of myeloid cells to promote endogenous immunity and tumor destruction. C57BL/6 mice bearing the ID8 ovarian tumor were treated with effector T cells transduced to express a chimeric NKG2D receptor. GM-CSF produced by the adoptively transferred T cells recruited peripheral F4/80loLy-6C+ cells to the tumor site in a CCR2-dependent fashion. T cell IFN-γ and GM-CSF activated tumor-associated macrophages, increased IL-12p40 production, and augmented antigen presentation by host macrophages to antigen-specific host T cells. In addition, host F4/80+ cells secreted the chemokines CXCL9 and CXCL10 and host T cells were recruited to the tumor site in a CXCR3-dependent manner. Endogenous CD8+ T cells, but not CD4+ T cells, were required for complete tumor elimination. However, host CD4+ T cells were critical for the development of a tumor-specific memory T cell response. These studies show that host macrophages activated by CAR-bearing T cell-derived cytokines inhibited ovarian tumor growth by directly lysing tumor cells and promoting host T cell immunity.