Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of experimental medicine, 2021-09, Vol.218 (9)

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.