Oncolytic alphavirus replicons mediated recruitment and activation of T cells

Darshak K Bhatt; Saskia L Meuleman; Baukje Nynke Hoogeboom; Toos Daemen

doi:10.1016/j.isci.2024.109253

Oncolytic alphavirus replicons mediated recruitment and activation of T cells

iScience. 2024 Feb 16;27(3):109253. doi: 10.1016/j.isci.2024.109253. eCollection 2024 Mar 15.

Authors

Darshak K Bhatt¹, Saskia L Meuleman¹, Baukje Nynke Hoogeboom¹, Toos Daemen¹

Affiliation

¹ Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.

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.

Keywords: Immunology; Virology.