As tumor PD-L1 provides signals to anti-tumor PD-1^(+)T cells that blunt their functions,αPD-1 andαPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis.Howeve...As tumor PD-L1 provides signals to anti-tumor PD-1^(+)T cells that blunt their functions,αPD-1 andαPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis.However,tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals,among other important effects.Tumor-initiating cells(TICs)generate carcinomas,resist treatments and promote relapse.We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells,TICs express more PD-L1 versus non-TICs.Silencing PD-L1 in B16 and ID8agg cells by shRNA(‘PD-L1lo’)reduced TIC numbers,the canonical TIC genes nanog and pou5f1(oct4),and functions as assessed by tumorosphere development,immune-dependent and immune-independent tumorigenesis,and serial transplantability in vivo.Strikingly,tumor PD-L1 sensitized TIC to interferon-γand rapamycin in vitro.Cell-intrinsic PD-L1 similarly drove functional TIC generation,canonical TIC gene expression and sensitivity to interferon-γand rapamycin in human ES2 ovarian cancer cells.Thus,tumor-intrinsic PD-L1 signals promote TIC generation and virulence,possibly by promoting canonical TIC gene expression,suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses.展开更多
基金This work was supported by grants CA170491,CA054174 and CDMRP from The Holly Beach Public LibraryThe Owens Foundation,The Ovarian Cancer Research Fund Alliance,The Barker Foundation and the Skinner endowment to Tyler Curiel.
文摘As tumor PD-L1 provides signals to anti-tumor PD-1^(+)T cells that blunt their functions,αPD-1 andαPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis.However,tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals,among other important effects.Tumor-initiating cells(TICs)generate carcinomas,resist treatments and promote relapse.We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells,TICs express more PD-L1 versus non-TICs.Silencing PD-L1 in B16 and ID8agg cells by shRNA(‘PD-L1lo’)reduced TIC numbers,the canonical TIC genes nanog and pou5f1(oct4),and functions as assessed by tumorosphere development,immune-dependent and immune-independent tumorigenesis,and serial transplantability in vivo.Strikingly,tumor PD-L1 sensitized TIC to interferon-γand rapamycin in vitro.Cell-intrinsic PD-L1 similarly drove functional TIC generation,canonical TIC gene expression and sensitivity to interferon-γand rapamycin in human ES2 ovarian cancer cells.Thus,tumor-intrinsic PD-L1 signals promote TIC generation and virulence,possibly by promoting canonical TIC gene expression,suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses.
