Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells

TLDR

Tumor‑specific T lymphocyte suppression limits immune surveillance, and although tumor‑recruited CD11b+ myeloid cells are known to mediate this dysfunction, their precise identity and the biochemical pathways underlying their immunosuppressive activity remain unclear. The study aims to identify and characterize a circulating population of CD11b+IL‑4Rα+ inflammatory monocytes that tumors elicit and that are activated by IFN‑γ from T lymphocytes. These CD11b+IL‑4Rα+ cells produce IL‑13 and IFN‑γ, integrating downstream cytokine signals to activate molecular pathways that suppress antigen‑activated CD8+ T lymphocytes. We found that analogous suppressive circuits operate in tumor‑resident CD11b+ cells, contradicting the notion that tumor‑conditioned immunosuppressive monocytes/macrophages are alternatively activated, and demonstrated that tumor‑induced inflammatory responses impair adaptive immunity, pointing to new therapeutic strategies for tumor‑induced immune dysfunction.

Abstract

Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor α+ (CD11b+IL-4Rα+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-γ released from T lymphocytes. CD11b+IL-4Rα+ cells produced IL-13 and IFN-γ and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.