Arenaviruses: Old viruses present new solutions for cancer therapy

Abstract

Viral-based cancer therapies have tremendous potential, especially in the context of treating poorly infiltrated cold tumors. However, in tumors with intact anti-viral interferon (IFN) pathways, while some oncolytic viruses induce strong innate and adaptive immune responses, they are neutralized before exerting their therapeutic effect. Arenaviruses, particularly the lymphocytic choriomeningitis virus (LCMV) is a noncytopathic virus with preferential cancer tropism and evolutionary mechanisms to escape the immune system for longer and to block early clearance. These escape mechanisms include inhibition of the MAVS dependent IFN pathway and spike protein antigen masking. Regarding its potential for cancer treatment, LCMV is therefore able to elicit long-term responses within the tumor microenvironment (TME), boost anti-tumor immune responses and polarize poorly infiltrating tumors towards a hot phenotype. Other arenaviruses including the attenuated Junin virus vaccine also have anti-tumor effects. Furthermore, the LCMV and Pichinde arenaviruses are currently being used to create vector-based vaccines with attenuated but replicating virus. This review focuses on highlighting the potential of arenaviruses as anti-cancer therapies. This includes providing a molecular understanding of its tropism as well as highlighting past and present preclinical and clinical applications of noncytophatic arenavirus therapies and their potential in bridging the gap in the treatment of cancers weakly responsive or unresponsive to oncolytic viruses. In summary, arenaviruses represent promising new therapies to broaden the arsenal of anti-tumor therapies for generating an immunogenic tumor microenvironment.

Keywords: LCMV (lymphocytic choriomeningitis virus); arenaviruses; cold tumors; immunomodualtors; noncytopathic virus; virotherapy.

Figure 1

Schematic representation of mammalian cell infection by LCMV is shown. (1) LCMV endocytosis is αDG-mediated and (2) leads to the release of viral genome in the cell cytoplasm. (3) NP, L and Z proteins are produced. Virus RNA activates RIG-1 and MDA5, however binding to MAVS and its activation is blocked by Z protein, therefore inhibiting the INF pathway. (4) GP precursor translation takes place in the endoplasmic reticulum and (5) maturates in Golgi by SKI-1/S1P mediated cleavage. (6) NP, L and Z proteins together with viral RNA assembly into virions with GP on the surface and (7) bud out of the infected cell. Figure was created with BioRender.com.

Figure 2

Schematic timeline representing arenavirus-based discoveries and research development is shown.

Figure 3

LCMV-based immunotherapies induce innate and adaptive immune responses within the tumor microenvironment. Attenuated but replicating artLCMV infects and activates APCs and delivers engineered tumor antigens for direct presentation to specific CD8⁺ T cells thereby inducing adaptive immune responses. Fibroblastic reticular cell infection by artLCMV leads to IL-33 secretion, activating the alarmin pathway in CD8⁺ T cells. LCMV directly replicates in tumor cells and APCs leading to pattern recognition receptors (PRR) activation and production of IFN-I in the TME. This leads to monocyte and cytotoxic CD8⁺ T cell recruitment, increased antigen presentation and MHC-I upregulation on tumor cells. LCMV also induces angiogenesis inhibiting TSP-1 surface expression on CD4⁺ and CD8⁺ T cells. Figure was created with BioRender.com.