BATF2 is a glutamine-responsive tumor suppressor essential for type I interferon-dependent anti-tumor immunity 2283

Abstract Description Recent evidence highlights the significance of a new type of tumor suppressors which are not frequently mutated but inhibited by metabolic cues in initiating cancers. Here we identify BATF2 as a novel tumor suppressor gene whose expression is epigenetically silenced by glutamine in the tumor microenvironment (TME). We utilized three cohorts of human squamous cell carcinomas to find that BATF2 correlates with type-I interferon (IFN-I) signatures, with even stronger correlation coefficients than a positive control, STING. As a molecular mechanism, we found that the phosphorylation of BATF2 at S227 promotes the phosphorylation and oligomerization of STING. BATF2 deficiency or high glutamine levels result in a metabolic profile unfavorable for IFN-I production. An isocaloric glutamine-rich diet dampens STING agonist-mediated tumor control, abolishing STING-mediated effector cell expansion in the TME. Cancer-specific BATF2 expression promotes an Id2-centered T-cell signature, reduces T-cell exhaustion, and triggers potent tumor rejection in an IFN-I and T-cell-dependent fashion. Utilizing syngeneic, orthotopic, and cigarette smoke carcinogen-induced squamous cell carcinoma models, we found that host deficiency of Batf2 results in increased infiltration of CD206+ myeloid cells and reduced CD8+ T-cells, accelerating cancer initiation. Overall, we reveal a new type of tumor suppressor BATF2 whose loss is mediated by metabolic cues in the TME and drives cancer immune escape. Funding Sources This work is supported by R01 DE026728, R01 DE030691, R01 DE031951, U01 DE033330, and U01 DE029255. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

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Publication Details

Journal
The Journal of Immunology
Published
2025-11-01
DOI
https://doi.org/10.1093/jimmun/vkaf283.218
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.00

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article

BATF2 is a glutamine-responsive tumor suppressor essential for type I interferon-dependent anti-tumor immunity 2283

Qiang Hu, Yu L. Lei, Shizuo Akira, Zhenhua Zhai et al.
The Journal of Immunology
interferon and immune responses
article

BATF2 is a glutamine-responsive tumor suppressor essential for type I interferon-dependent anti-tumor immunity 2283

Qiang Hu, Yu L. Lei, Shizuo Akira, Zhenhua Zhai, Shadmehr Demehri, Felipe Nör, Lei Wei, Andrew G. Sikora, Deepak Nagrath, Yuying Xie, Haitao Wen, Jiaqian Li, Kohei Okuyama, James J. Moon, Wang Gong, Christopher R. Donnelly, Zaiye Li, Zackary R. Fitzsimonds, Hülya F. Taner, Yuesong Wu, Gregory T. Wolf, Steven Bennett Chinn, Luke J. Broses, HE Yu-min, Emily Bellile, Yanbao Yu, Wanqing Cheng
article en

Abstract

Abstract Description Recent evidence highlights the significance of a new type of tumor suppressors which are not frequently mutated but inhibited by metabolic cues in initiating cancers. Here we identify BATF2 as a novel tumor suppressor gene whose expression is epigenetically silenced by glutamine in the tumor microenvironment (TME). We utilized three cohorts of human squamous cell carcinomas to find that BATF2 correlates with type-I interferon (IFN-I) signatures, with even stronger correlation coefficients than a positive control, STING. As a molecular mechanism, we found that the phosphorylation of BATF2 at S227 promotes the phosphorylation and oligomerization of STING. BATF2 deficiency or high glutamine levels result in a metabolic profile unfavorable for IFN-I production. An isocaloric glutamine-rich diet dampens STING agonist-mediated tumor control, abolishing STING-mediated effector cell expansion in the TME. Cancer-specific BATF2 expression promotes an Id2-centered T-cell signature, reduces T-cell exhaustion, and triggers potent tumor rejection in an IFN-I and T-cell-dependent fashion. Utilizing syngeneic, orthotopic, and cigarette smoke carcinogen-induced squamous cell carcinoma models, we found that host deficiency of Batf2 results in increased infiltration of CD206+ myeloid cells and reduced CD8+ T-cells, accelerating cancer initiation. Overall, we reveal a new type of tumor suppressor BATF2 whose loss is mediated by metabolic cues in the TME and drives cancer immune escape. Funding Sources This work is supported by R01 DE026728, R01 DE030691, R01 DE031951, U01 DE033330, and U01 DE029255. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

The Journal of ImmunologyVol. 214(Supplement_1)
The University of Texas MD Anderson Cancer Center (US), The Ohio State University (US)
Assisi Foundation of Memphis, St. Jude Children's Research Hospital, American Lebanese Syrian Associated Charities, National Institutes of Health
Openalex Percentile: Top 61%
interferon and immune responses
DOIOpen Access PDFOpenAlex
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