Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma

Abstract

PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in understanding of how to rationally leverage the therapeutic activity. PD-L1 is widely expressed in tumor cells but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1lo cells), which express basal PD-L1. We observed that PD-L1lo cells proliferated more weakly than control cells in vitro. As expected, PD-L1lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. A comparative microarray analysis identified a number of genes involved in autophagy and mTOR signaling that were affected by PD-L1 expression. In support of a functional role, PD-L1 attenuation augmented autophagy and blunted the ability of autophagy inhibitors to limit proliferation in vitro and in vivo in NSG mice. PD-L1 attenuation also elevated mTORC1 activity and augmented the anti-proliferative effects of the mTORC1 inhibitor rapamycin. PD-L1 cells were also relatively deficient in metastasis to the lung and we found that anti-PD-L1 administration could block tumor cell growth and metastasis in NSG mice. This therapeutic effect was observed with B16 cells but not ID8agg cells, illustrating tumor- or tissue-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate non-immune effects of anti-PD-L1 immunotherapy and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses.

Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy

“…A recent study indicates that PD-L1 may signal in tumor cells, such as ovarian cancer and melanoma, through a cancer cell-intrinsic, non-immune mechanism (Clark et al, 2016). No such data are available for PD-L2, which has not been extensively investigated in lung tumor models.…”

Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy

“…In addition to its immunopathogenesis role, the PD1/PD-L1 signaling pathway is recognized to play a key role in tumor intrinsic functions and survival 12. Autophagy is one example of these intrinsic functions affected by the PD-L1 ligand.…”

PD-L1 is a diverse molecule regulating both tumor-intrinsic signaling and adaptive immunosuppression

“…Although tumor-expressed PD-L1 induces immunosuppression of the adaptive tumor response, Clark et al , in their recent study in Cancer Research , demonstrated that PD-L1 and PD-1 also have tumor-intrinsic functions (8). They showed that PD-L1 impacted tumor cell biology via autophagy and mTOR and suggested that there are non-immune, broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses.…”