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Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer.

Publication ,  Journal Article
Gupta, HB; Clark, CA; Yuan, B; Sareddy, G; Pandeswara, S; Padron, AS; Hurez, V; Conejo-Garcia, J; Vadlamudi, R; Li, R; Curiel, TJ
Published in: Signal Transduct Target Ther
2016

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 (TIC) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TIC express more PD-L1 versus non-TIC. 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-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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Published In

Signal Transduct Target Ther

DOI

ISSN

2095-9907

Publication Date

2016

Volume

1

Start / End Page

16030-

Location

England

Related Subject Headings

  • 3101 Biochemistry and cell biology
 

Citation

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Gupta, H. B., Clark, C. A., Yuan, B., Sareddy, G., Pandeswara, S., Padron, A. S., … Curiel, T. J. (2016). Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther, 1, 16030-. https://doi.org/10.1038/sigtrans.2016.30
Gupta, Harshita B., Curtis A. Clark, Bin Yuan, Gangadhara Sareddy, Srilakshmi Pandeswara, Alvaro S. Padron, Vincent Hurez, et al. “Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer.Signal Transduct Target Ther 1 (2016): 16030-. https://doi.org/10.1038/sigtrans.2016.30.
Gupta HB, Clark CA, Yuan B, Sareddy G, Pandeswara S, Padron AS, et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther. 2016;1:16030-.
Gupta, Harshita B., et al. “Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer.Signal Transduct Target Ther, vol. 1, 2016, pp. 16030-. Pubmed, doi:10.1038/sigtrans.2016.30.
Gupta HB, Clark CA, Yuan B, Sareddy G, Pandeswara S, Padron AS, Hurez V, Conejo-Garcia J, Vadlamudi R, Li R, Curiel TJ. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther. 2016;1:16030-.

Published In

Signal Transduct Target Ther

DOI

ISSN

2095-9907

Publication Date

2016

Volume

1

Start / End Page

16030-

Location

England

Related Subject Headings

  • 3101 Biochemistry and cell biology