Journal Article

Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors

Kima, Rina, Thompson, Cynthia D., Lowy, Douglas R., Schiller, John T., Bialkowski, Lukasz, Çuburua, Nicolas, Pontejo, Sergio M., Bell, Alexander T. F., Sethi, Shiv K.

2022

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Anticancer properties / Antigens / Antitumor activity / Biological Sciences / CD4 antigen / CD8 antigen / Cell proliferation / Colon / Cytomegalovirus / Cytotoxicity / Epitopes / Immune clearance / Immunity / Immunology and Inflammation / Immunotherapy / INAUGURAL ARTICLE / Injection / Lymphocytes / Lymphocytes T / Melanoma / Metastases / Peptides / Polyinosinic:polycytidylic acid / Solid tumors / Tumor cells / Tumor microenvironment / Tumors