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 language | English |
|---|---|
| Pages (from-to) | 1978-1997 |
| Number of pages | 20 |
| Journal | Autophagy |
| Volume | 17 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2021 |
Bibliographical note
Funding Information:This work was supported by funding from the National Research Foundation of Korea (NRF-2017R1A2A1A17069818, NRF-2017R1D1A1B03035438, NRF-2019R1A4A1029000, NRF-2019M3A9A8066884 and NRF-2020R1A2C1007157) and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.
Funding Information:
Tissue samples were prospectively collected via surgery from the Department of Obstetrics and Gynecology of Gangnam Severance Hospital between 1996 and 2010. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea (NRF-2017M3A9B8069610). Tumor specimens from 398 patients with primary cervical cancer or cervical intraepithelial neoplasia (CIN) and 245 matched normal epithelium tissues were constructed into Tissue tissue microarrays (TMAs) as previously described []. Written informed consent was obtained from all patients who enrolled in this study. This study was approved by the Institutional Review Board of Gangnam Severance Hospital (Seoul, South Korea) and all procedures were conducted in accordance with the guidelines of the Declaration of Helsinki.
Publisher Copyright:
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology
