Department of Dermatology; RNA Therapeutics Institute; Program in Molecular Medicine; Department of Medicine, Division of Infectious Diseases and Immunology; Graduate School of Biomedical Sciences
Cancer Biology | Dermatology | Immunology and Infectious Disease | Neoplasms | Skin and Connective Tissue Diseases
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.
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DOI of Published Version
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
The Journal of experimental medicine
Fukuda K, Okamura K, Riding RL, Fan X, Afshari K, Haddadi N, McCauley SM, Guney MH, Luban J, Funakoshi T, Yaguchi T, Kawakami Y, Khvorova A, Fitzgerald KA, Harris JE. (2021). AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma. Open Access Publications by UMass Chan Authors. https://doi.org/10.1084/jem.20200962. Retrieved from https://escholarship.umassmed.edu/oapubs/4960
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This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.