Herpesvirus-based immunotherapies are emerging as exciting new possibilities for vaccines and cancer treatment. We have been exploring the use of a cytomegalovirus (CMV)-based cancer therapy to promote productive tumor-specific immunity and modify the tumor microenvironment. We previously showed that intratumoral (IT) infections with murine (M)CMV led to significant delays in the growth of B16 melanomas that were, surprisingly, independent of vaccine antigens encoded in the viral backbone. Although MCMV could infect B16 cells directly in vitro, tumor-associated macrophages (TAMs) were a primary target for viral infection in vivo. To test the mechanistic role of TAMs, we depleted monocytic phagocytes with clodronate. Loss of these myeloid cells completely prevented MCMV from delaying tumor growth. Macrophages are well-known targets of MCMV infection and in vitro studies demonstrated that MCMV infection of M2-polarized macrophages resulted in repolarization to an M1-like phenotype. In vivo, MCMV infection also increased expression of several inflammatory cytokines in the tumor. In a natural infection, MCMV uses the chemokine MCK-2 to recruit monocytes to the site of infection. Strikingly, MCMV deficient in MCK-2 was ineffective at delaying tumor growth. Further studies demonstrated that MCK-2 was necessary for MCMV to induce macrophage accumulation in the tumor and infiltration into the center of lesions. Finally, we found that repeated IT injections of MCMV caused more marked tumor growth delay and resulted in increased tumor clearance. Together, our results show that MCMV promotes tumor growth delay by modulation of the TAM compartment through recruitment of new macrophages via viral MCK-2 and infection of TAMs to promote an M1-like state within the tumor.
Citation Format: Nicole A. Wilski, Christina Del Casale, Vitali Alexeev, Constantine Daskalakis, Timothy J. Purwin, Andrew E. Aplin, Christopher M. Snyder. Cytomegalovirus infection of melanoma delays tumor growth by recruiting and altering monocytic phagocytes in the tumor [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A74.