Macrophage-derived IL10 indirectly suppresses CD8+ T-cell responses to chemotherapy.

  • Major finding: Macrophage-derived IL10 indirectly suppresses CD8+ T-cell responses to chemotherapy.

  • Mechanism: IL10 impairs CD8+ T-cell activity by repressing IL12 expression in intratumoral dendritic cells.

  • Impact: Inhibition of IL10R signaling may enhance the efficacy of cytotoxic chemotherapy.

Reducing macrophage infiltration through blockade of colony-stimulating factor 1 (CSF1) suppresses tumor growth when combined with chemotherapy in mouse models of mammary carcinoma via activation of CD8+ T cells. However, the mechanisms by which macrophages impair antitumor immune responses to chemotherapy are poorly understood. Ruffell and colleagues found that treatment of mice bearing mammary tumors with α-CSF1 antibody and paclitaxel reduced the expression of myeloid-associated genes in the tumor microenvironment, in particular the immunosuppressive cytokine IL10, which was primarily expressed by macrophages. In addition, IL10 expression in human breast cancers was correlated with genes associated with immunosuppressive TH2-type macrophage subsets. Accordingly, IL10 receptor (IL10R) blockade enhanced the tumor response to paclitaxel in a CD8+ T-cell–dependent manner, similar to the antitumor effects of α-CSF1 antibody. However, in contrast to α-CSF1 treatment, IL10R blockade did not inhibit macrophage recruitment to tumors or the ability of macrophages to suppress CD8+ T-cell proliferation, suggesting that IL10 indirectly inhibits CD8+ T-cell activity. Consistent with this idea, assessment of IL10R levels on tumor-infiltrating leukocytes revealed elevated expression on dendritic cells (DC) including CD103+ DCs, which exhibited increased recruitment into tumors in response to combined therapy with α-IL10R or α-CSF1 and paclitaxel. Mechanistically, administration of α-IL10R or α-CSF1 with paclitaxel resulted in the upregulation of IL12, a potent T-cell activator, in tumor-infiltrating CD103+ DCs, suggesting that IL10 regulates the DC phenotype and their expression of IL12. Indeed, macrophage-derived IL10 repressed Il12 mRNA expression in DCs, whereas IL12 blockade eliminated the improved response to chemotherapy associated with α-CSF1 or α-IL10R treatment. Further, increased expression of IL12A was correlated with expression of DC-associated transcription factors and increased pathologic complete response in patients with breast cancer. These findings elucidate the role of macrophage-produced IL10 in limiting cytotoxic T-cell responses and indicate that IL10 inhibition may enhance the efficacy of chemotherapy by increasing the maturation and functionality of IL12-expressing DCs in human breast cancer.

Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 2014;26:623–37.

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