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

• Published in: Autophagy Vol. 17; no. 8; pp. 1978 - 1997
• Main Authors: Kim, Suyeon, Cho, Hanbyoul, Hong, Soon-Oh, Oh, Se Jin, Lee, Hyo-Jung, Cho, Eunho, Woo, Seon Rang, Song, Joon Seon, Chung, Joon-Yong, Son, Sung Wook, Yoon, Sang Min, Jeon, Yu-Min, Jeon, Seunghyun, Yee, Cassian, Lee, Kyung-Mi, Hewitt, Stephen M., Kim, Jae-Hoon, Song, Kwon-Ho, Kim, Tae Woo
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03-08-2021
• Subjects: Animals; Autophagy - genetics; Cancer immunoediting; Cell Line, Tumor; EGFR; ErbB Receptors - metabolism; Humans; immune resistance; immunotherapy; LC3B; MAP1LC3B; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; NANOG; Nanog Homeobox Protein - metabolism; Neoplastic Stem Cells - metabolism; Research Paper; Signal Transduction - genetics; Up-Regulation; Cancer immunoediting; MAP1LC3B; LC3B; immune resistance; immunotherapy; NANOG; EGFR
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2020.1805214

Immune selection drives tumor cells to acquire refractory phenotypes. We previously demonstrated that cytotoxic T lymphocyte (CTL)-mediated immune pressure enriches NANOG
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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
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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
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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
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immune-refractory cancer.
Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A
1
; 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