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 4

Morphological and functional characterization of tumor-induced CD11b+IL-4Rα+ and CD11b+IL-4Rα– cells.

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Morphological and functional characterization of tumor-induced CD11b+IL-...
Splenocytes were sorted by microbeads to select CD11b+ cells, and this cellular population was subsequently sorted by flow cytometry to select IL-4Rα+ (left panels) and IL-4Rα– (right panels) cells. (A) The sorted cells were stained with H&E and May-Grünwald-Giemsa stain (M-GG). Pictures were taken under microscopy at ×40 magnification. CD11b+IL-4Rα+ cells showed a monocytic morphology, while CD11b+IL-4Rα– cells comprised granulocytes at various differentiation stages, including immature cells with band morphology. (B) Both populations were analyzed by flow cytometry for their expression of IL-13 (top panels) and IFN-γ (bottom panels). Open histograms indicate staining with IL-13 or IFN-γ antibody; filled histograms indicate isotype-matched antibody control. Data are representative of at least 3 determinations in separate experiments. (C) The 2 populations were added at a final concentration of 3% to alloantigen-stimulated cultures (see above). CD11b+IL-4Rα+ but not CD11b+IL-4Rα– cells suppressed the generation of alloreactive CTLs (P < 0.01 and P = 0.48, respectively). Results are shown as the fraction of LU30 measured in the control allo-cultures lacking third-party CD11b+ cells. Data are mean ± SEM from 3 experiments.