Firing up the cold tumors by targeting Vps34

Abstract

Cancer immunotherapy based on anti-PD-1/PD-L1 blockade is particularly effective in responding to patients with hot tumors. These tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration. In our recent report published in Science Advances, we demonstrate that targeting the autophagy-related protein Vps34 switched cold immune desert tumors into hot inflamed immune-infiltrated tumors and enhanced the efficacy of anti-PD-1/PD-L1. Our study provides the preclinical rationale to set up combination immunotherapy clinical trials using selective Vps34 inhibitors and immune checkpoint blockers in melanoma and CRC.

Keywords: Autophagy; CCL5; CXCL10; NK cells; T CD8 lymphocytes; VPS34; anti-PD-1/PD-L1; cancer immunotherapy; cold/hot tumors; colon cancer; immune landscape; melanoma; proinflammatory cytokines.

Figure 1.

Vps34 inhibition improves anti-PD-1/PD-L1 immunotherapy by switching cold into hot tumors. Cold tumors are characterized by the absence of immune cells or the limited number of cytotoxic immune cells in the tumor microenvironment. Therefore, cold tumors are not eligible or most likely not responding to immunotherapy (1). Treatment of cold tumors with Vps34 inhibitors (2) induces the release by tumor cells of proinflammatory chemokines such as CCL5 and CXCL10. These chemokines drives more NK and CD8 T cells to the tumor microenvironment. Vps34i-treated tumors become hot and therefore eligible to anti-PD-1/PD-L1 based immunotherapy (3). Combined Vps34i with anti-PD-1/PD-L1 (4) improves the therapeutic benefit of immunotherapy and significantly decreases the tumor growth.