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

Keitaro Fukuda, Ken Okamura, Rebecca L. Riding, Xueli Fan, Khashayar Afshari, Nazgol Sadat Haddadi, Sean M. McCauley, Mehmet H. Guney, Jeremy Luban, Takeru Funakoshi, Tomonori Yaguchi, Yutaka Kawakami, Anastasia Khvorova, Katherine A. Fitzgerald, John E. Harris

研究成果: Article査読

22 被引用数 (Scopus)


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.

ジャーナルJournal of Experimental Medicine
出版ステータスPublished - 2021 7月 29

ASJC Scopus subject areas

  • 医学(全般)


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