The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma
Open accessAbstract
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-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. 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-L1lo 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.
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Cites
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FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
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Metadata
- Authors
- Clark, C. A., Gupta, H. B., Sareddy, G., Pandeswara, S., Lao, S., Yuan, B., Drerup, J. M., Padron, A., Conejo-Garcia, J., Murthy, K., Liu, Y., Turk, M. J., Thedieck, K., Hurez, V., Li, R., Vadlamudi, R., & Curiel, T. J.
- Venue
- Cancer Research
- Published
- 2016-11-30
- Volume
- 76
- Issue
- 23
- Pages
- 6964-6974
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2523826139
- Cited by
- 391
- References
- 16
- FWCI
- 15.30
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Clark, C. A., Gupta, H. B., Sareddy, G., Pandeswara, S., Lao, S., Yuan, B., Drerup, J. M., Padron, A., Conejo-Garcia, J., Murthy, K., Liu, Y., Turk, M. J., Thedieck, K., Hurez, V., Li, R., Vadlamudi, R., & Curiel, T. J. (2016). Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma. Cancer Research. https://doi.org/10.1158/0008-5472.can-16-0258
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