Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells
Giovanna Gallina, … , Silvio Bicciato, Vincenzo Bronte
Giovanna Gallina, … , Silvio Bicciato, Vincenzo Bronte
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2777-2790. https://doi.org/10.1172/JCI28828.
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Research Article Oncology

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

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.

Authors

Giovanna Gallina, Luigi Dolcetti, Paolo Serafini, Carmela De Santo, Ilaria Marigo, Mario P. Colombo, Giuseppe Basso, Frank Brombacher, Ivan Borrello, Paola Zanovello, Silvio Bicciato, Vincenzo Bronte

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Figure 9

Mechanisms of MSC-dependent suppression.

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Mechanisms of MSC-dependent suppression. In the “triggering phase,” T ly...
In the “triggering phase,” T lymphocytes activated by exposure to the antigen release IFN-γ that, possibly in conjunction with a not yet identified membrane signal, activates inflammatory monocyte precursors. Whereas in resting condition this would result in induction of classically activated macrophages, monocytes conditioned by tumors show a different program because of the expression of IL-4Rα and the ability to release both IL-13 and IFN-γ. The IFN-γ production, initially sustained by activated T lymphocytes, is subsequently amplified by the cytokine released from activated monocytes. IFN-γ allows the prolonged expression and signaling of IL-4Rα after engagement by IL-13 released via an autocrine circuit. During the “amplification phase,” the cytokines are thus able to maintain a prolonged activation of the enzymes NOS and ARG, which ultimately originate the immunosuppressive mediators acting on the CD8+ T cells. This model supports the view that a prolonged stimulation of MSCs is necessary to mediate a full inhibition of CD8+ T cells and explains why T cells can initially proliferate in the presence of spleen-derived MSCs. On the other hand, ARG and NOS are constitutively activated in tumor-infiltrating MSCs, which account for the prompt immunosuppression provided by these cells (Figure 1).