Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes

Purpose: Adaptation to host immune surveillance is now recognized as a hallmark of cancer onset and progression, and represents an early, indispensable event in cancer evolution. This process of evolution is first instigated by an immune selection pressure imposed by natural host surveillance mechanisms and may then be propagated by vaccination or other types of immunotherapy. Experimental Design: We developed a system to simulate cancer evolution in a live host and to dissect the mechanisms responsible for adaptation to immune selection. Here, we show that the oxygen-sensitive a subunit of hypoxia-inducible factor 1 (HIF-1a) plays a central role in cancer immune adaptation under conditions of normal oxygen tension. Results: We found that tumor cells gain HIF-1a in the course of immune selection under normoxia and that HIF- 1a renders tumor cells resistant to lysis by tumor-specifi c cytotoxic T lymphocytes (CTL) in culture and in mice. The effects of HIF-1α on immune adaptation were mediated through VEGFA-dependent activation of the AKT and ERK signaling pathways, which induced an antiapoptotic gene expression network in tumor cells. Conclusions: Our study therefore establishes a link between immune selection, overexpression of HIF-1a, and cancer immune adaptation under normoxia, providing new opportunities for molecular intervention in patients with cancer.