Open AccessAIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma
Author(s) -
Keitaro Fukuda,
Ken Okamura,
Rebecca L. Riding,
Xin Fan,
Khashayar Afshari,
NazgolSadat Haddadi,
Sean Matthew McCauley,
Mehmet Hakan Guney,
Jeremy Luban,
Takeru Funakoshi,
Tomonori Yaguchi,
Yutaka Kawakami,
Anastasia Khvorova,
Katherine A. Fitzgerald,
John E. Harris
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20200962
Subject(s) - aim2 , immunotherapy , melanoma , cancer research , adoptive cell transfer , tumor microenvironment , cd8 , immunology , immune system , biology , cancer immunotherapy , t cell , innate immune system
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.