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

Authors

Keitaro Fukuda, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Ken Okamura, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Rebecca L. Riding, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Xueli Fan, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Khashayar Afshari, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Nazgol-Sadat Haddadi, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.
Sean M. McCauley, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Mehmet H. Guney, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Jeremy Luban, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
Takeru Funakoshi, Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
Tomonori Yaguchi, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Yutaka Kawakami, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Anastasia Khvorova, RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA.
Katherine A. Fitzgerald, Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA.
John E. Harris, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.

Document Type

Article

Publication Title

The Journal of experimental medicine

Abstract

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.

DOI

10.1084/jem.20200962

Publication Date

9-6-2021

Recommended Citation

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.; and Harris, John E., "AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma" (2021). Internal Medicine. 302.
https://scholar.bridgeporthospital.org/internal_medicine/302

Identifier

34325468 (pubmed); PMC8329870 (pmc); 10.1084/jem.20200962 (doi); 212521 (pii)