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

Autor:	Clark CA; The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Gupta HB; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Sareddy G; Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.; Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas., Pandeswara S; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Lao S; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Yuan B; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Drerup JM; The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Padron A; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Conejo-Garcia J; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Murthy K; The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Liu Y; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.; Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China., Turk MJ; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire., Thedieck K; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands and Department for Neuroscience, School of Medicine and Health Sciences, University Oldenburg, Oldenburg, Germany., Hurez V; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Li R; The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.; Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Vadlamudi R; The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.; Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.; Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas., Curiel TJ; The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas. curielt@uthscsa.edu.; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.; Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2016 Dec 01; Vol. 76 (23), pp. 6964-6974. Date of Electronic Publication: 2016 Sep 26.
DOI:	10.1158/0008-5472.CAN-16-0258
Abstrakt:	PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in the understanding of how to rationally leverage 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-L1 lo cells), which express basal PD-L1. We observed that PD-L1 lo cells proliferated more weakly than control cells in vitro As expected, PD-L1 lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. RNA sequencing 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 reduced mTORC1 activity and augmented the antiproliferative effects of the mTORC1 inhibitor rapamycin. PD-L1 lo 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 compartmental-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate nonimmune effects of anti-PD-L1 immunotherapy, and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses. Cancer Res; 76(23); 6964-74. ©2016 AACR. Competing Interests: The authors have no conflicting financial interests to declare. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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