Lian and Nie et al. showed that LCMV gp66-specific CD4+ T cells inhibited tumor growth in an MC38-GP model in an antigen-specific manner, independent of direct lymphoid cell-mediated cytotoxicity. CD4+ T cells initiated antigen-dependent perivascular, myeloid cell-dense structures in the TIME, reprogrammed myeloid transcriptomes, and leveraged recruited myeloid cells to control tumor growth. Single-cell and spatial transcriptomics showed that CD4+ T cell-derived IL-3 programmed macrophages to secrete tumor necrosis factor, which damaged intratumoral vasculature, compromised blood supply, and induced localized tumor cell death and regression.
Contributed by Shishir Pant
ABSTRACT: Most cancer immunotherapy strategies are focused on direct tumor killing by immune cells, especially T lymphocytes. Clinical and conceptual limitations of these approaches create a need for additional strategies. We identified a tumor stroma-targeting mechanism in which tumor antigen-specific CD4(+) T cells inhibit tumor growth through myeloid cell and tumor necrosis factor (TNF)-dependent vascular damage. Multiplex immunofluorescence and single-cell and tissue transcriptomics showed that CD4(+) T cells trigger the formation of perivascular myeloid cell clusters containing "classically activated" macrophages that produce TNF in response to T cell-derived interleukin-3. TNF causes intratumoral endothelial damage and blood supply disruption, which are associated with localized tumor cell death. Thus, intratumoral antigen-triggered T cell activation can mediate antitumor effects without direct recognition of living tumor cells, thereby avoiding many of the inhibitory mechanisms that limit anti-tumor immunity.
