Oncolytic alphavirus replicons mediated recruitment and activation of T cells

TL;DR

This paper shows that alphavirus-based replicons can boost immune responses in tumors, especially when encoding cytokines like IFN-γ, even in less responsive cancer cells.

Contribution

The study introduces cytokine-encoding alphavirus replicons that enhance tumor immunogenicity across different cancer cell types.

Findings

rSFV replicons effectively express transgenes in both tumor monolayer and spheroid models.

Cytokine-encoding replicons, especially IFN-γ, enhance immune responses regardless of cancer cell susceptibility.

LNCaP cells show higher infection rates and immune activation compared to PANC-1 cells.

Abstract

Oncolytic viruses show promise in enhancing tumor immunogenicity by releasing immunogenic signals during tumor cell infection and lysis. In this study, we improved the virus-induced tumor immunogenicity of recombinant Semliki Forest virus (rSFV)-based replicon particles by encoding immunogenic cytokines such as C-X-C motif chemokine ligand 10 (CXCL10), FMS-like tyrosine kinase 3 ligand (Flt3L), or interferon-gamma (IFN-ƴ). Real-time imaging and flow cytometry of human cancer cell-based monolayer and spheroid cultures, using LNCaP or PANC-1 cells, revealed effective infection and transgene expression in both models. LNCaP cells exhibited higher and earlier rSFV infection compared to PANC-1 cells. While infected LNCaP cells effectively triggered immune recruitment and T cell activation even without encoding cytokines, PANC-1 cells demonstrated improved immune responses only when infected with replicons encoding cytokines, particularly IFN-ƴ, which enhanced tumor immunogenicity irrespective of cancer cell susceptibility to infection. Our study demonstrates that despite innate phenotypic disparities in cancer cells, rSFV-based replicons encoding cytokines can potentially generate effective immune responses in the tumor.

•rSFV-replicons effectively express transgenes in tumor monolayer and spheroids•rSFV-replicons can induce transgene-independent immune recruitment and activation•Innate disparities in antiviral response influence immune activation by tumor cells•rSFV-replicons encoding cytokines enhance immune responses across tumor types

rSFV-replicons effectively express transgenes in tumor monolayer and spheroids

rSFV-replicons can induce transgene-independent immune recruitment and activation

Innate disparities in antiviral response influence immune activation by tumor cells

rSFV-replicons encoding cytokines enhance immune responses across tumor types

Immunology; Virology

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