Background: Immunotherapy has become a novel paradigm in cancer treatment in the past decade, with significant clinical responses in a subset of cancer patients. However, a considerable subset of patients are unresponsive or relapse following the initial response. Hypoxia-inducible factors (HIFs) have been identified as a major contributing factor to immunotherapy unresponsiveness. HIFs activate crucial proliferation pathways that contribute to the promotion of an immunosuppressive tumor microenvironment (TME) and subsequent tumor growth, survival, and immune escape. The Raf kinase inhibitor protein (RKIP) can inhibit these oncogenic pathways; however, RKIP is often under-expressed in most cancers. Hypothesis: We hypothesized that RKIP negatively regulates HIF-1 expression and that the induction of RKIP counteracts HIF-induced immune evasion by inhibiting oncogenic signaling pathways including MAPK, NF-κB, and PI3K. This establishes the RKIP/HIF-1 axis in cancer cells and its targeting to restore anti-cancer immunotherapy. Aims & Methods: We investigated the following: (1) the mechanisms underlying HIF-1-mediated immune evasion (2) the bidirectional regulation of RKIP and HIF-1 and (3) potential approaches to induce RKIP as a means to overcome HIF-related immune evasion mechanisms. Results: This review indicated a bidirectional regulation of RKIP and HIF in cancer, which has notable implications for tumor immune evasion. HIF-1 contributes to immune evasion by upregulating multiple oncogenic signaling pathways in addition to immune checkpoint molecules. HIF-1-mediated induction of survival signaling pathways negatively regulates RKIP expression and further amplifies HIF activation. Conversely, RKIP induction inhibits these signaling pathways and reduces HIF activation and its oncogenic properties. These findings established the RKIP/HIF-1 axis in cancer cells and its targeting potential. Conclusions: Our findings illustrate that RKIP successfully counteracts HIF-induced immune evasion mechanisms through its blockage of oncogenic signaling pathways. RKIP-induced inhibition of HIF-1 expression is an effective means of decreasing tumor immune escape. Hence, we have established the RKIP/HIF-1 axis as a highly relevant axis in cancer therapeutics and suggest the use of RKIP induction therapy in combination with current treatment to overcome immune evasion.
PCO25-216: The RKIP/HIF-1 Axis in Cancer Immune Evasion
Authors:
and
Ryan Mcwhorter
BA
Ryan Mcwhorter
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, CA
Search for other papers by Ryan Mcwhorter in
Current site
Google Scholar
PubMed
Search for other papers by Ryan Mcwhorter in
Current site
Google Scholar
PubMed
Benjamin Bonavida
PhD
Benjamin Bonavida
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, CA
Search for other papers by Benjamin Bonavida in
Current site
Google Scholar
PubMed
Search for other papers by Benjamin Bonavida in
Current site
Google Scholar
PubMed
© 2019-2024 National Comprehensive Cancer Network