Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8 þ Tcell responses. Furthermore, we found that IL-17A was produced mainly by Vg4 gd T cells, insofar as depleting Vg4 gd T cells reduced tumor growth, whereas adoptive transfer of Vg4 gd T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing gd T cells via production of IL-1b and IL-23. Conversely, IL-17A could also enhance production of IL-1b and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among gd T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. Cancer Res; 74(7); 1969-82. Ó2014 AACR.

No abstract

Blockade of PD-L1 expression on tumor cells via anti-PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; however, the function of PD-L1 on natural killer (NK) cells and the effects of anti-PD-L1 mAb on PD-L1 + NK cells remain unknown. Moreover, patients with PD-L1 − tumors can respond favorably to anti-PD-L1 mAb therapy for unclear reasons. Here, we show that some tumors can induce PD-L1 on NK cells via AKT signaling, resulting in enhanced NK-cell function and preventing cell exhaustion. Anti-PD-L1 mAb directly acts on PD-L1 + NK cells against PD-L1 − tumors via a p38 pathway. Combination therapy with anti-PD-L1 mAb and NK cell-activating cytokines significantly improves the therapeutic efficacy of human NK cells against PD-L1 − human leukemia when compared with monotherapy. Our discovery of a PD-1-independent mechanism of antitumor efficacy via the activation of PD-L1 + NK cells with anti-PD-L1 mAb offers new insights into NK-cell activation and provides a potential explanation as to why some patients lacking PD-L1 expression on tumor cells still respond to anti-PD-L1 mAb therapy.