Open AccessBladder cancer cell‐intrinsic PD‐L1 signals promote mTOR and autophagy activation that can be inhibited to improve cytotoxic chemotherapy
Author(s) -
Zhang Deyi,
Reyes Ryan M.,
Osta Erica,
Kari Suresh,
Gupta Harshita B.,
Padron Alvaro S.,
Kornepati Anand V. R.,
Kancharla Aravind,
Sun Xiujie,
Deng Yilun,
Wu Bogang,
Vadlamudi Ratna,
Li Rong,
Svatek Robert S.,
Curiel Tyler J.
Publication year - 2021
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.3739
Subject(s) - autophagy , cancer research , mtorc1 , melanoma , ovarian cancer , pi3k/akt/mtor pathway , in vivo , cancer , cell growth , cytotoxic t cell , cell , cancer cell , apoptosis , medicine , biology , signal transduction , in vitro , microbiology and biotechnology , biochemistry , genetics
Tumor cell‐intrinsic programmed death‐ligand 1 (PD‐L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell‐intrinsic PD‐L1 signals in mouse MB49 and human RT4, UM‐UC3, and UM‐UC‐14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α‐PD‐L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell‐intrinsic PD‐L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune‐independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell‐intrinsic PD‐L1 signals also promoted basal and stress‐induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell‐intrinsic PD‐L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis‐platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell‐intrinsic PD‐L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof‐of‐concept, we showed that the autophagy inhibitor chloroquine improved cis‐platinum treatment efficacy in vivo, with greater efficacy in PD‐L1 null versus PD‐L1‐replete BC.