Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species

Abstract

Tumor growth is associated with the accumulation of immature myeloid cells (ImC), which in mice are characterized by the expression of Gr-1 and CD11b markers. These cells suppress Ag-specific CD8+ T cells via direct cell-cell contact. However, the mechanism of immunosuppressive activity of tumor-derived ImC remains unclear. In this study we analyzed the function of ImC isolated from tumor-free control and tumor-bearing mice. Only ImC isolated from tumor-bearing mice, not those from their control counterparts, were able to inhibit the Ag-specific response of CD8+ T cells. ImC obtained from tumor-bearing mice had significantly higher levels of reactive oxygen species (ROS) than ImC isolated from tumor-free animals. Accumulation of H2O2, but not superoxide or NO, was a major contributor to this increased pool of ROS. It appears that arginase activity played an important role in H2O2 accumulation in these cells. Inhibition of ROS in ImC completely abrogated the inhibitory effect of these cells on T cells, indicating that ImC generated in tumor-bearing hosts suppress the CD8+ T cell response via production of ROS. Interaction of ImC with Ag-specific T cells in the presence of specific Ags resulted in a significant increase in ROS production compared with control Ags. That increase was independent of IFN-γ production by T cells, but was mediated by integrins CD11b, CD18, and CD29. Blocking of these integrins with specific Abs abrogated ROS production and ImC-mediated suppression of CD8+ T cell responses. This study demonstrates a new mechanism of Ag-specific T cell inhibition mediated by ROS produced by ImCs in cancer.

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

“…ROS production disrupts TCR signaling and it has been reported that reducing ROS releases CD8 T cell suppression by MDSC. 42 This mechanism appears to underlie the effects of RT/IL-12 on MDSC-mediated T cell suppression, as ROS production from tumor-infiltrating MDSCs only decreased when the tumor was treated with RT in combination with IL-12, but not with RT or with IL-12 alone (Figure 7(b,c). Another potential effect of combination therapy on MDSCs is to promote their further differentiation towards macrophages and DCs, as observed in TLR-7/8 agonist-stimulated MDSCs.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…T cells further increase the activity of neutrophils through secretion of IFNγ. The increase in oxygen radicals have additional effects, such as suppression of T cell responses [278,384], activation of TGFβ [81], and induction of GMP-140 (P-Selectin) expression on the surface of endothelial cells, leading to enhanced neutrophil adherence and activity [385]. The activation of TGFβ suppresses excessive neutrophil function, and may polarize them into N2 neutrophils [13].…”

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

“…Gr-1 ϩ IMC freshly isolated from spleen of tumor-bearing mice could not inhibit CD4-mediated T cell response, but were able to suppress CD8 ϩ T cells in Ag-dependent manner (16). This inhibition required direct cell-cell contact and was mediated by reactive oxygen species (19). Interestingly, when Gr-1 ϩ cells were incubated for several days in vitro, they acquired ability to block CD4-mediated T cell responses (20).…”