Cited by 256Autophagy in Disease and TherapyCancer, Hypoxia, and MetabolismCancer Immunotherapy and Biomarkers

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Blocking Hypoxia-Induced Autophagy in Tumors Restores Cytotoxic T-Cell Activity and Promotes Regression

Noman, Muhammad Zaeem, Janji, Bassam, Kaminska, Bozena, Van Moer, Kris, Pierson, Sandrine, Przanowski, Piotr, Buart, Stéphanie, Berchem, Guy, Romero, Pedro, Mami-Chouaib, Fathia, Chouaib, Salem·2011·Cancer Research

DOI 10.1158/0008-5472.can-11-1094

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Abstract

The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)–mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth. Cancer Res; 71(18); 5976–86. ©2011 AACR.

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Authors: Noman, M. Z., Janji, B., Kaminska, B., Van Moer, K., Pierson, S., Przanowski, P., Buart, S., Berchem, G., Romero, P., Mami-Chouaib, F., & Chouaib, S.
Affiliations: Inserm (FR)
Authors' Affiliations: 1Unité INSERM U753, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, France; 2Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé), Luxembourg City, Luxembourg; 3Laboratory of Transcription Regulation, Department of Cell Biology, Nencki Institute, Warsaw, Poland; and 4Translational Tumor Immunology group, Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland
ORCID: Noman, Muhammad Zaeem
Janji, Bassam
Przanowski, Piotr
Buart, Stéphanie
Berchem, Guy
Romero, Pedro
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-09-13
Volume: 71
Issue: 18
Pages: 5976-5986
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-11-1094
OpenAlex: W2151713424
Cited by: 256
References: 44
Citations by year: 2026: 8 · 2025: 2 · 2024: 15 · 2023: 15 · 2022: 30 · 2021: 30 · 2020: 24 · 2019: 16 · 2018: 16 · 2017: 16 · 2016: 23 · 2015: 11 · 2014: 14 · 2013: 19 · 2012: 12
FWCI: 12.00
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: tumor hypoxia, autophagy, cytotoxic T lymphocytes, STAT3 phosphorylation, HIF-1α, Beclin-1, ATG5, Src kinase, ubiquitin-proteasome system, p62, tumor regression, B16F10 melanoma, hydroxychloroquine, tumor immunology
MeSH terms: Sequestosome-1 Protein, Animals, Autophagy, Heat-Shock Proteins, Humans, Lung Neoplasms, Melanoma, Experimental, Mice, Inbred C57BL, Phosphorylation, T-Lymphocytes, Cytotoxic, Cell Hypoxia, src-Family Kinases, Ubiquitin, Cell Line, Tumor, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, STAT3 Transcription Factor, Mice

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Blocking Hypoxia-Induced Autophagy in Tumors Restores Cytotoxic T-Cell Activity and Promotes Regression

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