TY - JOUR
T1 - Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer
AU - Gupta, Harshita B.
AU - Clark, Curtis A.
AU - Yuan, Bin
AU - Sareddy, Gangadhara
AU - Pandeswara, Srilakshmi
AU - Padron, Alvaro S.
AU - Hurez, Vincent
AU - Conejo-Garcia, José
AU - Vadlamudi, Ratna
AU - Li, Rong
AU - Curiel, Tyler J.
N1 - Funding Information:
We thank Andrew Brenner for help in establishing tumorosphere cultures. This work was supported by grants CA170491, CA054174 and CDMRP from The Holly Beach Public Library, The Owens Foundation, The Ovarian Cancer Research Fund Alliance, The Barker Foundation and the Skinner endowment to Tyler Curiel.
PY - 2016
Y1 - 2016
N2 - As tumor PD-L1 provides signals to anti-tumor PD-1 + T cells that blunt their functions, αPD-1 and αPD-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-L1 lo ’) 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-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and 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.
AB - As tumor PD-L1 provides signals to anti-tumor PD-1 + T cells that blunt their functions, αPD-1 and αPD-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-L1 lo ’) 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-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and 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.
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U2 - 10.1038/sigtrans.2016.30
DO - 10.1038/sigtrans.2016.30
M3 - Article
AN - SCOPUS:85026827596
VL - 1
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
SN - 2095-9907
M1 - 16030
ER -