AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.

Autor:	Fukuda K; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.; Department of Dermatology, Keio University School of Medicine, Tokyo, Japan., Okamura K; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA., Riding RL; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA., Fan X; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA., Afshari K; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA., Haddadi NS; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA., McCauley SM; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA., Guney MH; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA., Luban J; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA., Funakoshi T; Department of Dermatology, Keio University School of Medicine, Tokyo, Japan., Yaguchi T; Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan., Kawakami Y; Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA.; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA., Fitzgerald KA; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA., Harris JE; Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2021 Sep 06; Vol. 218 (9). Date of Electronic Publication: 2021 Jul 29.
DOI:	10.1084/jem.20200962
Abstrakt:	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-1β 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. Competing Interests: Disclosures:   K. Fukuda, K.A. Fitzgerald, A. Khvorova, and J.E. Harris have filed a patent that covers AIM2 siRNAs and their use to treat melanoma. The authors declare no other competing interests. (© 2021 Fukuda et al.)
Databáze:	MEDLINE
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