Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING

Blake R Heath; Wang Gong; Hülya F Taner; Luke Broses; Kohei Okuyama; Wanqing Cheng; Max Jin; Zackary R Fitzsimonds; Andriana Manousidaki; Yuesong Wu; Shaoping Zhang; Haitao Wen; Steven B Chinn; Eric Bartee; Yuying Xie; James J Moon; Yu Leo Lei

doi:10.1016/j.celrep.2023.112303

Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING

Cell Rep. 2023 Apr 25;42(4):112303. doi: 10.1016/j.celrep.2023.112303. Epub 2023 Mar 22.

Authors

Blake R Heath¹, Wang Gong², Hülya F Taner³, Luke Broses², Kohei Okuyama², Wanqing Cheng⁴, Max Jin⁵, Zackary R Fitzsimonds⁴, Andriana Manousidaki⁶, Yuesong Wu⁶, Shaoping Zhang⁷, Haitao Wen⁸, Steven B Chinn⁹, Eric Bartee¹⁰, Yuying Xie⁶, James J Moon¹¹, Yu Leo Lei¹²

Affiliations

¹ Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA.
² Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
³ Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Oral Health Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
⁴ Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA.
⁵ Homer Stryker M.D. School of Medicine, Western Michigan University, Kalamazoo, MI, USA.
⁶ Department of Computational Mathematics, Science, and Engineering, Department of Statistics, Michigan State University, East Lansing, MI, USA.
⁷ Department of Periodontics, University of Iowa College of Dentistry, Iowa City, IA, USA.
⁸ Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA.
⁹ University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI, USA.
¹⁰ Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
¹¹ Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA.
¹² Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Graduate Program in Oral Health Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: leiyuleo@umich.edu.

Abstract

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.

Keywords: CP: Cancer; CP: Immunology; NLRC3; STING; head and neck cancer; immunogenicity; innate immunity; metabolism; obesity; saturated fatty acids; type-I interferon.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Fatty Acids
Head and Neck Neoplasms*
Interferon Type I* / metabolism
Mice
Myeloid Cells / metabolism
Squamous Cell Carcinoma of Head and Neck
Tumor Microenvironment

Substances

Fatty Acids
Interferon Type I

Abstract

Publication types

MeSH terms

Substances

Grants and funding