Murine Cytomegalovirus Promotes Anti-tumor Immunity in a Melanoma Model by Recruiting Macrophages and Inducing Inflammation through STING Signaling

Abstract

Cytomegalovirus (CMV) has emerged as a promising vector for cancer vaccines due to its ability to generate a robust CD8+ T cell response against tumor antigens encoded in the backbone when using murine (M)CMV in preclinical models. However, there is also conflicting literature in the field concerning CMV as a tumor resident pathogen with multiple groups reporting that CMV may promote tumor aggressiveness in glioblastoma and ovarian cancer. Thus, moving forward, it is incredibly important to understand the interactions between CMV and the tumor microenvironment. We have investigated the mechanism of action of an active MCMV infection in a B16-F0 melanoma model. In this model, wild type MCMV promotes anti-tumor immunity which correlates with the time the virus is actively producing viral transcript. We show that recruitment of macrophages via the viral chemokine MCK2 and subsequent infection and activation of STING signaling is required to promote an anti-tumor effect. In vitro, MCMV was able to re-polarize M2-like macrophages to become more M1-like, and was also able to induce inflammatory cytokine production in the tumor microenvironment. Loss of STING signaling in vivo resulted in impaired IFN-α and CXCL10 production as well as loss of tumor control. We hypothesize here that type-I IFN produced by STING signaling is necessary to induce inflammatory changes in the tumor microenvironment and promote anti-tumor immunity. Thus, we put forth for the first time that an active MCMV infection in the tumor increases immune infiltration into immune dessert B16-F0 lesions and acts as a STING agonist to alter the inflammatory microenvironment of the tumor. Along with the data from other labs indicating CMV plays an unfavorable role in tumor progression, our work suggests that CMV may have differing effects on the tumor microenvironment depending on viral tropism and activation status in the tumors. In the context of an active viral infection in macrophages, we show that CMV shows promise as a cancer immunotherapy in the clinic either alone or as an adjuvant to increase infiltration into immune poor environments