The implications of oncolytic viruses targeting fibroblasts in enhancing the antitumoural immune response

Abstract

Oncolytic viruses (OVs) are an emerging immunotherapy platform that selectively target tumour cells, inducing immunogenic cell death. This reverses the 'immune-desert' phenotype of tumours, enhancing antitumour immunity. However, oncolytic virotherapy has shown limited efficacy in solid tumours due to the presence of protumoural, immunosuppressive cancer-associated fibroblasts (CAFs). Recent studies have explored OVs that specifically target CAFs to enhance antitumoural immune responses, with promising results. Nevertheless, detailed interrogation of the experimental design of these studies casts doubt on their potential for successful clinical translation. Most studies targeted CAFs non-specifically, failing to acknowledge CAF heterogeneity, with antitumoural CAFs also present. Thus, use of transcriptomics is advisable to provide more focused targeting, limiting potential off-target toxicity. Furthermore, experiments to date have largely been conducted in murine models that do not faithfully recapitulate tumour microenvironments, potentially biasing the efficacy observed. Future work should make use of humanised patient-derived xenograft murine models for animal studies, after which primary human tumour biopsies should be utilised to more closely represent the patient population for maximal translation relevance. Additionally, approaches to enhance the antitumoural immune responses of this therapy should be prioritised, with the ultimate aim of achieving complete remission, which has not yet been observed pre-clinically.

Keywords: Anti-tumoural immunity; Cancer-associated fibroblast; Immunotherapy; Oncolytic virus.

Fig. 1

– Schematic of CAF activation and their protumoural effects. Adapted from “Mechanisms of Cancer-associated Fibroblast Activation”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates.

Fig. 2

Potential avenues towards optimising CAF-targeting OV design to shift the equilibrium of the TME in favour of antitumoural CAFs. (A) Recognition of CAF heterogeneity through selective targeting of protumoural CAFs and minimising off-target effects towards antitumoural CAFs. Exposure of the extent of CAF-heterogeneity may be uncovered through multi-omic approaches, especially transcriptomic analysis for biomarkers and molecular signatures within the recognised CAF subtypes. (B) Exploiting factors that facilitate plasticity of protumoural CAF subtypes towards antitumoural subtypes. ∗Antitumoural CAFs are those in which antitumoural activity has been observed although their predominant phenotype is undetermined. Created in BioRender.com.

Fig. 3

– Five prospective strategies for improving future CAF-targeting OV therapies. These are discussed in further detail below. (A) CAF plasticity can be exploited through the use of different signalling pathways to convert protumoural CAFs into an antitumoural phenotype, an example of which could be through inhibiting JAK/STAT signalling in protumoural CAFs. (B) Technological advancements in the form of nanotechnology and CRISPR can be utilised to increase the precision of OV targeting of CAFs, reducing off-target effects and furthering efficacy. (C) Future clinical trials are required in order to assess the safety of CAF-targeting OVs, as well as analysing patient tumoural landscapes in order to enable personalisation of therapy, both of which aim to improve treatment outcomes. (D) Combination therapies will likely play a key role in this field to synergise with the OV therapy to overcome the immunosuppressive TME. This will involve therapies such as immune checkpoint blockade, enzymes to degrade immunosuppressive ECM proteins, and cytokines to reactivate immune cells from an anergic state. (E) The identification of future targetable biomarkers and signalling pathways is essential for increasing our understanding of how to better target CAFs, particularly protumoural ones. These targets could be identified through multiple approaches, including the study of genetically modified murine models and transcriptomic analysis of CAFs from patient tumour biopsies. Created in BioRender. Al-obaidi, I. (2024) BioRender.com/u27b713.