Abstract

Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. New therapeutic approaches that induce a strong and prolonged immune activation would represent a major immunotherapeutic advance. Here we show that the arenaviruses lymphocytic choriomeningitis virus (LCMV) and the clinically used Junin virus vaccine (Candid#1) preferentially replicate in tumour cells in a variety of murine and human cancer models. Viral replication leads to prolonged local immune activation, rapid regression of localized and metastatic cancers, and long-term disease control. Mechanistically, LCMV induces antitumour immunity, which depends on the recruitment of interferon-producing Ly6C+ monocytes and additionally enhances tumour-specific CD8+ T cells. In comparison with other clinically evaluated oncolytic viruses and to PD-1 blockade, LCMV treatment shows promising antitumoural benefits. In conclusion, therapeutically administered arenavirus replicates in cancer cells and induces tumour regression by enhancing local immune responses.

Highlights

  • Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity

  • We show that lymphocytic choriomeningitis virus (LCMV) and Candid#1 preferentially replicate in cancer cells and induce immune surveillance resulting in IFN-I-dependent tumour regression

  • As cancer cells are characterized by altered cell cycle, metabolism and translation[16] relative to their normal counterparts, we wondered whether arenaviruses might preferentially replicate in tumour cells and whether this affects the antitumoural immune response

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Summary

Introduction

Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. We show that the arenaviruses lymphocytic choriomeningitis virus (LCMV) and the clinically used Junin virus vaccine (Candid#1) preferentially replicate in tumour cells in a variety of murine and human cancer models. Therapeutically administered arenavirus replicates in cancer cells and induces tumour regression by enhancing local immune responses. The immune system can directly attack tumour cells via antigen-specific cytotoxic CD8 þ T cells, activated natural killer (NK) cells or antibody-mediated cytotoxicity[2,3]. Effective induction of strong and sustained immune activation at the tumour sites would be a promising therapeutic approach against cancer. The non-cytopathic arenaviruses propagate rapidly without directly harming susceptible tissues Rather, it is the immune response against infected cells that may cause severe tissue damage and disease symptoms[8,9]. Recombinant single-cycle LCMV is considered a vaccine virus with potential to immunize against tumour antigens[15]

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