Tumor-intrinsic B7-H1 in melanoma and ovarian cancer regulates mTOR, autophagy and tumor growth

Abstract

Abstract Tumor B7-H1 (PD-L1) promotes tumor immune evasion by interaction with T cell PD-1. B16 melanoma and ID8agg ovarian cancer express B7-H1. We genetically made B7-H1lo or B7-H1hi lines to study additional B7-H1 effects. Control B16 and ID8agg grew more rapidly in vitro versus B7-H1lo cells and B7-H1hi B16 cells grew faster than control. In vivo, B16 and ID8agg grew faster than B7-H1lo lines in immunodeficient NSG mice. B16 challenge in NSG mice with B7-H1hi cells produced more lung metastases versus parental, which produced more metastases than B7-H1lo. αB7-H1 significantly reduced tumor growth and metastases. These data support an immune-independent role for tumor B7-H1 in tumor growth and metastatic spread. Control B16 and ID8agg cells had elevated TORC1 and reduced TORC2 versus B7-H1lo cells. The mTOR inhibitor rapamycin reduced cell growth greater in parental versus B7-H1lo cells in vitro. Also in line with reduced TORC1, B7-H1lo cells had increased autophagy (LC3-II/actin ratio and autophagosome formation) compared to parental cells. Notably, autophagy inhibitors chloroquine and 3-methyladenine had a greater inhibitory effect on in vitro proliferation of control B16 versus B7-H1lo cells. Inhibition of autophagy in vivo with either agent significantly reduced tumor growth of B16 but not B7-H1lo cells, suggesting that B7-H1 replete tumors are more dependent on the stress-modulating function of autophagy versus B7-H1lo tumors. Our studies show novel tumor-intrinsic B7-H1 signal effects that regulate mTOR and autophagy signals directly associated with immune-independent tumor growth, supporting a paradigm shifting concept that tumor B7-H1 augments stress response and metabolism through cell-intrinsic mechanisms.