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Gain of HIF-1 alpha under Normoxia in Cancer Mediates Immune Adaptation through the AKT/ERK and VEGFA Axes

Authors
Lee, Young-HoBae, Hyun CheolNoh, Kyung HeeSong, Kwon-HoYe, Sang-kyuMao, Chih-PingLee, Kyung-MiWu, T. -C.Kim, Tae Woo
Issue Date
15-3월-2015
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CLINICAL CANCER RESEARCH, v.21, no.6, pp.1438 - 1446
Indexed
SCIE
SCOPUS
Journal Title
CLINICAL CANCER RESEARCH
Volume
21
Number
6
Start Page
1438
End Page
1446
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/94128
DOI
10.1158/1078-0432.CCR-14-1979
ISSN
1078-0432
Abstract
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-1 alpha) plays a central role in cancer immune adaptation under conditions of normal oxygen tension. Results: We found that tumor cells gain HIF-1 alpha in the course of immune selection under normoxia and that HIF-1 alpha renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice. The effects of HIF-1 alpha 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-1 alpha, and cancer immune adaptation under normoxia, providing new opportunities for molecular intervention in patients with cancer. (C) 2015 AACR.
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