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

Harshita B. Gupta, Curtis A. Clark, Bin Yuan, Gangadhara Sareddy, Srilakshmi Pandeswara, Alvaro S. Padron, Vincent Hurez, José Conejo-Garcia, Ratna Vadlamudi, Rong Li, Tyler J. Curiel

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number16030
JournalSignal Transduction and Targeted Therapy
Volume1
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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