TY - JOUR TI - LC3B upregulation by NANOG promotes immune resistance and stem-like property through hyperactivation of EGFR signaling in immune-refractory tumor cells AU - Kim, Suyeon AU - Cho, Hanbyoul AU - Hong, Soon-Oh AU - Oh, Se Jin AU - Lee, Hyo-Jung AU - Cho, Eunho AU - Woo, Seon Rang AU - Song, Joon Seon AU - Chung, Joon-Yong AU - Son, Sung Wook AU - Yoon, Sang Min AU - Jeon, Yu-Min AU - Jeon, Seunghyun AU - Yee, Cassian AU - Lee, Kyung-Mi AU - Hewitt, Stephen M. AU - Kim, Jae-Hoon AU - Song, Kwon-Ho AU - Kim, Tae Woo T2 - Autophagy AB - 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. DA - 2020/08/07/ PY - 2020 DO - 10.1080/15548627.2020.1805214 DP - Taylor and Francis+NEJM VL - 0 IS - ja SP - null SN - 1554-8627 UR - https://doi.org/10.1080/15548627.2020.1805214 Y2 - 2020/08/10/18:10:55 KW - EGFR KW - LC3B KW - MAP1LC3B KW - NANOG KW - cancer immunoediting KW - immune resistance KW - immunotherapy ER -