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 6

Adoptive cell transfer is effective only in mice with a myeloid-restricted inactivation of IL-4Rα.

Options: View larger image (or click on image) Download as PowerPoint
Adoptive cell transfer is effective only in mice with a myeloid-restrict...
(A) LysMCreIL-4R–/flox mice and control littermates were challenged s.c. on day 0 with C26-GM cells and were given, 24 hours later, CD8+ T cells purified from the spleens and lymph nodes of mice vaccinated 14 days before with γ-irradiated C26-GM cells. Tumor size is indicated as the product of the 2 main perpendicular diameters measured with a caliper. Mice with tumors had to be euthanized on day 12, since they were showing severe signs of distress. (B) The CD3+CD8+ cells positive for the Ld tetramer loaded with AH1 peptide were determined in the blood of tumor-bearing mice 8 days after tumor inoculation. One dot plot for each group is reported. Numbers indicate the percentages of AH1-TET+ cells among gated CD3+CD8+ T lymphocytes (mean ± SEM, n = 5–6). (C) The absolute numbers of CD3+CD8+AH1-TET+ cells were calculated for the total number of circulating white blood cells (WBCs) and reported as mean ± SEM. The background staining given by control β-gal876–884/Ld TET was subtracted for each determination. (D) IFN-γ–/– and WT BALB/c mice were challenged s.c. on day 0 with C26-GM cells and given, 24 hours later, CD8+ T cells purified from the spleens and lymph nodes of IFN-γ–/– and WT BALB/c mice, vaccinated 14 days before with γ-irradiated C26-GM cells. Results, expressed as survival rates after tumor challenge, are from 1 representative experiment with 6 mice per group.