Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness
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David R. Soto-Pantoja1,3, Adam S. Wilson1, Kenysha YJ. Clear1, Brian Westwood1, Pierre L. Triozzi2,3 and Katherine L. Cook1,3
1Department of Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
2Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
3Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
Katherine L. Cook, email: [email protected]
Keywords: breast cancer, melanoma, immune therapy, ipilimumab, CTLA4
Received: March 22, 2017 Accepted: July 23, 2017 Published: August 03, 2017
The unfolded protein response (UPR) is a stress pathway controlled by GRP78 to mediate IRE1, PERK, and ATF6 signaling. We show that targeting GRP78, IRE1, and PERK differentially regulates macrophage polarization. Specifically, PERK targeting enhanced macrophage proliferation and macrophage-mediated killing but not GRP78 or IRE1. Targeting UPR in cancer cells also differentially affected macrophage cytolytic capacity. Tumoral IRE1 or GRP78 inhibition enhanced macrophage-mediated cancer cell clearance. Conditioned media from GRP78-silenced cancer cells caused reciprocal regulation of CD80 and CD206, suggesting control of plasticity by secreted factors. GRP78 targeting in mice resulted in a cytokine shift and increased tumoral CD80+/CD68+ cells, suggesting an M1-like profile. Targeting UPR in both macrophage and cancer cells indicates that PERK or GRP78 reduction enhances macrophage clearance of cancer cells. Recent evidence suggests that macrophage polarization influences immune checkpoint therapy resistance. To determine whether UPR effects immunotherapy resistance, analysis of matched melanoma patient PBMC before/after developing ipilimumab resistance demonstrated increased UPR signaling and an M2-like macrophage population, supporting a novel role of UPR signaling and innate immune regulation in anti-CTLA-4 therapy resistance. These data suggest that targeting GRP78 or PERK promotes an anti-tumor immune response by either directly promoting macrophage cytolytic activity or indirectly by shifting tumoral cytokine secretion.
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