Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression

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.

Viral infection overcomes ineffectiveness of anti-tumoral CD8+ T cell mediated cytotoxicity

“…Therefore, we reasoned that revealed that accumulation and activation of intratumoral CD8 + T effector cells was enhanced by LCMV infection, suggesting that the limited infiltration of CD8 + T cells observed in B16F10-OVA melanoma recovered by LCMV. We have previously shown that LCMV can replicate in many tumor models [9], which strongly support that LCMV and Junín virus vaccine, Candid#1 reversed the MHC class I expression. We discovered that LCMV treatment promoted the proliferation of CD8 + T cells in draining LNs, and LCMV combined PD-1 cocktail significantly reduced tumor growth compared to LCMV treatment alone (data not show).…”

“…Type I and type II interferon signaling contribute to the upregulation of MHC-I on tumor cells [28,[48][49][50]. In our previous studies [9] we showed that replicating arenaviruses induce a strong interferon response via the activation of the innate immune response. Therefore, we reasoned that revealed that accumulation and activation of intratumoral CD8 + T effector cells was enhanced by LCMV infection, suggesting that the limited infiltration of CD8 + T cells observed in B16F10-OVA melanoma recovered by LCMV.…”

“…Advanced neoplasms acquire several properties to escape from the host's immune system leading to invasion of the tumor. Immune evasion mechanisms include dysregulation of the antigen presentation pathways, exhaustion of T cells, release of negative regulatory signals and recruitment of immunosuppressive cells to the tumor microenvironment supporting the establishment of the immune tolerance to cancer cells [6][7][8][9][10][11]. The immunogenic tolerance to tumors limits the effects of the anticancer chemotherapy and irradiation [12][13][14].…”

“…Cancer cells are a good target for non-oncolytic viruses which replicate selectively and activate immune defenses against tumor cells without harming normal tissue [30,31]. In mouse models, previous research showed that acute infections with WE strain of lymphocytic choriomeningitis virus (LCMV-WE) exert antitumor effects [9,32,33]. Beside these principal inflammatory stimuli, LCMV can be used as a vaccine vector to immunize against tumor antigens [34][35][36][37].…”

Sustained Type I Interferon Reinforces NK Cell–Mediated Cancer Immunosurveillance during Chronic Virus Infection

“…The mechanism of virotherapy is not yet fully understood, but it can be broadly divided into the recruitment and activation of immune cells by inflammatory cytokines and the direct lysis of tumor cells. According to a published study (47), nononcolytic LCMV showed superior anticancer effects compared with the oncolytic vesicular stomatitis virus widely used in virotherapy. Kalkavan and colleagues found that locally or systemically administered LCMV preferentially replicated in cancer cells, causing Ly6C þ monocytes to secrete type I IFNs, resulting in the activation of tumorspecific CD8 þ T cells and tumor regression (47).…”