한빛사논문
- 조회1,342
Suyeon Kim1,2, Hanbyoul Cho3,4,5, Soon-Oh Hong1,2, Se Jin Oh1,2, Hyo-Jung Lee1,2, Eunho Cho1,2, Seon Rang Woo1,2, Joon Seon Song6, Joon-Yong Chung3, Sung Wook Son1,2, Sang Min Yoon7, Yu-Min Jeon7, Seunghyun Jeon1,2, Cassian Yee8, Kyung-Mi Lee1,2, Stephen M Hewitt3, Jae-Hoon Kim4,5, Kwon-Ho Song1,2,*, Tae Woo Kim1,2,*
1Department of Biochemistry & Molecular Biology, Department of Biomedical Science, Korea University College of Medicine , Seoul, South Korea.
2Department of Biomedical Science, Korea University College of Medicine , Seoul, South Korea.
3Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892, USA.
4Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea.
5Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
6Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
7Korea University College of Medicine, Seoul, South Korea.
8Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
*Corresponding author
Abstract
Immune selection drives tumor cells to acquire refractory phenotypes. We previously demonstrated that cytotoxic T lymphocyte (CTL)-mediated immune pressure enriches NANOG+ tumor cells with stem-like and immune-refractory properties that make them resistant to CTLs. Here, we report that the emergence of refractory phenotypes is highly associated with an aberrant macroautophagic/autophagic state of the NANOG+ tumor cells and that the autophagic phenotype arises through transcriptional induction of MAP1LC3B/LC3B by NANOG. Furthermore, we found that upregulation of LC3B expression contributes to an increase in EGF secretion. The subsequent hyperactivation of EGFR-AKT signaling rendered NANOG+ tumor cells resistant to CTL killing. The NANOG-LC3B-p-EGFR axis was preserved across various types of human cancer and correlated negatively with the overall survival of cervical cancer patients. Inhibition of LC3B in immune-refractory tumor models rendered tumors susceptible to adoptive T-cell transfer, as well as PDCD1/PD-1 blockade, and led to successful, long-term control of the disease. Thus, our findings demonstrate a novel link among immune-resistance, stem-like phenotypes, and LC3B-mediated autophagic secretion in immune-refractory tumor cells, and implicate the LC3B-p-EGFR axis as a central molecular target for controlling NANOG+ immune-refractory cancer.
논문정보
- Research article
- 2020년 08월 (BRIC 등록일 2020-08-12)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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