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

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

IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts

Background/Aims: Unexpected transmissions of viral pathogens during solid organ transplantation (SOT) can result in severe, life-threatening diseases in transplant recipients. Immune activation contributes to disease onset. However mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. Methods & Results: Here we found, using lymphocytic choriomeningitis virus (LCMV), that transplantation of LCMV infected hearts led to exhaustion of virus specific CD8(+) T cells, viral persistence in organs and survival of graft and recipient. Genetic depletion of Interleukin-10 (IL-10) resulted in strong immune activation, graft dysfunction and death of mice, suggesting that IL-10 was a major regulator of CD8(+) T cell exhaustion during SOT. In the presence of memory CD8(+) T cells, virus could be controlled. However sufficient antiviral immune response resulted in acute rejection of transplanted heart. Conclusion: We found that virus transmitted via SOT could not be controlled by naive mice recipients due to IL-10 mediated CD8(+) T cell exhaustion which thereby prevented immunopathology and graft failure whereas memory mice recipients were able to control the virus and induced graft failure. (C) 2016 The Author(s) Published by S. Karger AG, Base

High Frequencies of Anti-Host Reactive CD8(+) T Cells Ignore Non-Hematopoietic Antigen after Bone Marrow Transplantation in a Murine Model

Background: Graft versus host disease (GvHD) occurs in 20% of cases with patients having an MHC I matched bone marrow transplantation (BMT). Mechanisms causing this disease remain to be studied. Methods: Here we used a CD8(+) T cell transgenic mouse line (P14/CD45.1(+)) and transgenic DEE mice bearing ubiquitously the glycoprotein 33-41 (GP33) antigen derived from the major lymphocytic choriomeningitis virus (LCMV) epitope to study mechanisms of tolerance in anti-host reactive CD8(+) T cells after BMT. Results: We found that anti-host reactive CD8(+) T cells (P14 T cells) were not negatively selected in the thymus and that they were present in wild type (WT) recipient mice as well as in DEE recipient mice. Anti host reactive CD8(+) T cells ignored the GP33 antigen expressed ubiquitously by host cells but they could be activated ex vivo via LCMV-infection. Lipopolysaccha rides (LPS) induced transient cell damage in DEE mice bearing anti-host reactive CD8(+) T cells after BMT, suggesting that induction of host inflammatory response could break antigen ignorance. Introducing the GP33 antigen into BM cells led to deletion of anti-host reactive CD8(+) T cells. Conclusion: We found that after BMT anti-host reactive CD8(+) T cells ignored host antigen in recipients and that they were only deleted when host antigen was present in hematopoietic cells. Moreover, [PS-induced immune activation contributed to induction of alloreactivity of anti-host reactive CD8(+) T cells after BMT. Copyright (C) 2016 S. Karger AG, Base

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

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