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.
View: Text | PDF
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

×

Figure 5

Phenotypic characterization of tumor-induced CD11b+IL-4Rα+ cells.

Options: View larger image (or click on image) Download as PowerPoint
Phenotypic characterization of tumor-induced CD11b+IL-4Rα+ cells. ...
(A) CD11b+ cells from spleens of mice inoculated 9 days earlier with C26-GM tumor cell lines were enriched through immunomagnetic microbeads and stained with the indicated antibody. FS, forward scatter; SS, side scatter. (B) Blood cells (top rows) and spleen cells (bottom rows) from mice of various strains inoculated with different tumors were stained for CD11b and IL-4Rα. The following tumor cell lines were used: the BALB/c-derived colon carcinoma CT26 (closely related to the C26 tumor used in our previous experiments) and mammary carcinoma 4T1; and the C57BL/6–derived EL-4 lymphoma and MCA203 fibrosarcoma. Data are from a single experiment representative of 3. (C) CD11b+ cells were sorted from the spleens of tumor-bearing WT or KO BALB/c mice and added at a final concentration of 3% to a mixed leukocyte culture set up as previously described (top panels). CD11b+ cells sorted from the spleens of tumor-bearing C57BL/6 mice were added at a final concentration of 3% to a mixed leukocyte culture set up with C57BL/6 effectors stimulated with an equal number of γ-irradiated BALB/c splenocytes, in the presence or absence of anti–IFN-γ and/or anti–IL-13 mAbs added at the beginning and at the third day of culture (bottom panels).