Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 26; pp. 1 - e2116738119
• Main Authors: Çuburu, Nicolas, Bialkowski, Lukasz, Pontejo, Sergio M., Sethi, Shiv K., Bell, Alexander T. F., Kim, Rina, Thompson, Cynthia D., Lowy, Douglas R., Schiller, John T.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 28.06.2022
• Series: Inaugural Article
• Subjects: Anticancer properties; Antigens; Antitumor activity; Biological Sciences; CD4 antigen; CD8 antigen; Cell proliferation; Colon; Cytomegalovirus; Cytotoxicity; Epitopes; Immune clearance; Immunity; Immunotherapy; Injection; Lymphocytes; Lymphocytes T; Melanoma; Metastases; Peptides; Polyinosinic:polycytidylic acid; Solid tumors; Tumor cells; Tumor microenvironment; Tumors; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2116738119

Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4 + or CD8 + T cells. The MCMV CD8 + T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4 + T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen–specific CD8 + T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8 + T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8 + T cell–peptide epitopes alone or CD4 + T cell–peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen–agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.