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 1

MSCs inhibit antigen-induced T lymphocyte proliferation but not IFN-γ release.

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MSCs inhibit antigen-induced T lymphocyte proliferation but not IFN-γ re...
(A) CFSE-labeled splenocytes derived from mice transferred with HA-specific CD8+ (CL4) T cells and primed with HA-encoding vaccinia virus were stimulated with the HA peptide in the absence (No CD11b) or in the presence of CD11b+ cells magnetically purified from either the spleen or the tumor infiltrate of tumor-bearing mice and admixed at a 1:10 ratio. The cultures were stimulated for 60 hours with the relevant peptide, and the clonotypic proliferation was evaluated as CFSE dilution by flow cytometry. (B) Data are presented as the mean percentage of CL4 cells in each cycle from triplicate wells (± SEM); 1 of 2 representative experiments is reported. (C) MSCs do not suppress IFN-γ production from naive or antigen-experienced (memory) CD8+ T cells. MSCs were isolated from the spleens of normal or tumor-bearing mice, and 6 × 105 cells were admixed with 3 × 106 splenocytes containing naive (2.4 × 105) or in vivo antigen-experienced (2.1 × 105) HA-specific CD8+ T cells stimulated with the relevant peptide in an ELISPOT assay. Data (mean ± SEM) are derived from triplicate wells of 1 representative experiment.