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.
AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma
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.
- Award Id(s): AR069114
- Award Id(s): S10 OD020012
- Views Icon Views
- Share Icon Share
- Search Site
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; AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma. J Exp Med 6 September 2021; 218 (9): e20200962. doi: https://doi.org/10.1084/jem.20200962
Download citation file: