LC3B upregulation by NANOG promotes immune resistance and stem-like property through hyperactivation of EGFR signaling in immune-refractory tumor cells

Suyeon Kim, Hanbyoul Cho, Soon Oh Hong, Se Jin Oh, Hyo Jung Lee, Eunho Cho, Seon Rang Woo, Joon Seon Song, Joon Yong Chung, Sung Wook Son, Sang Min Yoon, Yu Min Jeon, Seunghyun Jeon, Cassian Yee, Kyung Mi Lee, Stephen M. Hewitt, Jae Hoon Kim, Kwon Ho Song, Tae Woo Kim

Research output: Contribution to journalArticle

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. Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A1; CASP3: caspase 3; CFSE: carboxyfluorescein succinimidyl ester; ChIP: chromatin immunoprecipitation; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CSC: cancer stem cell; CTL: cytotoxic T lymphocyte; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FIGO: International Federation of Gynecology and Obstetrics; GFP: green fluorescent protein; GZMB: granzyme B; HG-CIN: high-grade CIN; IHC: immunohistochemistry; LG-CIN: low-grade CIN; LN: lymph node; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCL1: myeloid cell leukemia sequence 1; MLANA/MART-1: melanoma antigen recognized by T cells 1; MUT: mutant; NANOG: Nanog homeobox; PDCD1/PD-1: programmed cell death 1; PMEL/gp100: premelanosome protein; RTK: receptor tyrosine kinase; TMA: tissue microarray; WT: wild type.

Original languageEnglish
JournalAutophagy
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • Cancer immunoediting
  • EGFR
  • immune resistance
  • immunotherapy
  • LC3B
  • MAP1LC3B
  • NANOG

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kim, S., Cho, H., Hong, S. O., Oh, S. J., Lee, H. J., Cho, E., Woo, S. R., Song, J. S., Chung, J. Y., Son, S. W., Yoon, S. M., Jeon, Y. M., Jeon, S., Yee, C., Lee, K. M., Hewitt, S. M., Kim, J. H., Song, K. H., & Kim, T. W. (Accepted/In press). LC3B upregulation by NANOG promotes immune resistance and stem-like property through hyperactivation of EGFR signaling in immune-refractory tumor cells. Autophagy. https://doi.org/10.1080/15548627.2020.1805214