Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer

Lisa A Santry; Jacob P van Vloten; Amanda W K AuYeung; Robert C Mould; Jacob G E Yates; Thomas M McAusland; James J Petrik; Pierre P Major; Byram W Bridle; Sarah K Wootton

doi:10.3389/fmicb.2024.1325558

Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer

Front Microbiol. 2024 Jan 24:15:1325558. doi: 10.3389/fmicb.2024.1325558. eCollection 2024.

Affiliations

¹ Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
² Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
³ Juravinski Cancer Center, Hamilton, ON, Canada.

Abstract

Introduction: Tumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs).

Methods: To reverse this immunosuppression, we engineered mesogenic Newcastle disease virus (NDV) to express immunological checkpoint inhibitors anti-cytotoxic T lymphocyte antigen-4 and soluble programmed death protein-1.

Results: Intratumoral administration of recombinant NDV (rNDV) to mice bearing intradermal B16-F10 melanomas or subcutaneous CT26LacZ colon carcinomas led to significant changes in the tumor-infiltrating lymphocyte profiles. Vectorizing immunological checkpoint inhibitors in NDV increased activation of intratumoral natural killer cells and cytotoxic T cells and decreased Tregs and MDSCs, suggesting induction of a pro-inflammatory state with greater infiltration of activated CD8+ T cells. These notable changes translated to higher ratios of activated effector/suppressor tumor-infiltrating lymphocytes in both cancer models, which is a promising prognostic marker. Whereas all rNDV-treated groups showed evidence of tumor regression and increased survival in the CT26LacZ and B16-F10, only treatment with NDV expressing immunological checkpoint blockades led to complete responses compared to tumors treated with NDV only.

Discussion: These data demonstrated that NDV expressing immunological checkpoint inhibitors could reverse the immunosuppressive state of tumor microenvironments and enhance tumor-specific T cell responses.

Keywords: B16-F10; Newcastle disease virus (NDV); PD-1; PD-L1; anti-CTLA-4; immunological checkpoint inhibitors; oncolytic virus; tumor microenvironment.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Funding was provided by Discovery Grants from the Natural Sciences and Engineering Research Council (NSERC) of Canada to SW (#499834) and BB (#04069), Operating Grants from the Cancer Research Society to SW (#946085) and BB (#843296), and an Operating Grant jointly funded by the Canadian Institutes of Health Research (CIHR) (#159395) and Cancer Research Society (#25222) to BB and SW. Stipend support was provided by the Ontario Veterinary College (OVC) (LS, JV, AA, RM, and JY), the Ontario Graduate Scholarship program (LS and JV), the NSERC Postgraduate Scholarship-Doctoral program (LS), a Canadian Graduate Scholarship-Master’s Award from CIHR (AA), and an OVC Pet Trust Scholar’s Program Award (AA). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.