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Blocking Hypoxia-Induced Autophagy in Tumors Restores Cytotoxic T-Cell Activity and Promotes Regression
Published version of a preprint
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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In the citing paper
“Normoxic and hypoxic stabilization of HIF signaling in tumor cells promotes resistance to cytotoxic T lymphocyte–mediated lysis”
From Hypoxic control of metastasis (2016) · cites this paper as [54]
In the citing paper
“the increased resistance of hypoxic tumor cells to CTL-mediated lysis. This increased resistance to CD8 T cell-mediated killing is correlated with the hypoxic induction of tumor cell autophagy [86, 87].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [87]
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Metadata
- 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
- Venue
- Cancer Research
- Published
- 2011-09-13
- Volume
- 71
- Issue
- 18
- Pages
- 5976-5986
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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