UMMS Affiliation

Department of Dermatology; RNA Therapeutics Institute; Program in Molecular Medicine; Department of Medicine, Division of Infectious Diseases and Immunology; Graduate School of Biomedical Sciences

Publication Date

2021-07-29

Document Type

Article

Disciplines

Cancer Biology | Dermatology | Immunology and Infectious Disease | Neoplasms | Skin and Connective Tissue Diseases

Abstract

The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti-PD-1 immunotherapy for "cold tumors," which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1beta and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.

Keywords

Tumor immunology

Rights and Permissions

Copyright © 2021 Fukuda et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

DOI of Published Version

10.1084/jem.20200962

Source

Fukuda K, Okamura K, Riding RL, Fan X, Afshari K, Haddadi NS, McCauley SM, Guney MH, Luban J, Funakoshi T, Yaguchi T, Kawakami Y, Khvorova A, Fitzgerald KA, Harris JE. AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma. J Exp Med. 2021 Sep 6;218(9):e20200962. doi: 10.1084/jem.20200962. Epub 2021 Jul 29. PMID: 34325468; PMCID: PMC8329870. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of experimental medicine

Related Resources

Link to Article in PubMed

PubMed ID

34325468

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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