Abstract 5249: Macrophages expressing synthetic cytokine receptors reverse IL10-mediated immunosuppression within solid tumors and promote adaptive immunity
Authors: Chris Sloas, Silvia Beghi, Yuhao Huangfu, Rehman Qureshi, Benjamin Schott, Michael Ball, Daniel Blumenthal, Thomas Condamine, Michael Klichinsky, Yumi Ohtani
Journal: Cancer Research (2024)

Abstract Motivation: In solid tumors, anti-inflammatory cytokines such as IL10 and TGFβ support an immunosuppressive tumor microenvironment (TME) and inhibit anti-tumor immunity. Many therapeutic approaches to overcome immunosuppression have used monoclonal antibodies to block cytokine signaling. Instead of silencing TME-associated cytokines, a more powerful strategy may be to leverage them as disease markers and convert them into anti-tumor signals, using a logic-gated cell-based immunotherapy. Here, we engineered macrophages with synthetic cytokine switch receptors (SR) that convert IL10 or TGFβ into pro-inflammatory signals. Macrophages are homeostatic regulators capable of both infiltrating solid tumors and initiating inflammation, and we harnessed this proficiency using SRs that convert prevalent cytokines in the TME into pro-inflammatory responses for TME modulation. We termed this engineered myeloid cell platform “Engineered Microenvironment Converters” (EM-C) and evaluated its ability to overcome cytokine-mediated immunosuppression in solid tumors. Methods: EM-C were produced by transducing primary macrophages or monocytes with a SR that converts IL10 into an interferon-based signal. The response of EM-C to IL10 was monitored in vitro using phenotypic characterization of surface molecules, measurement of secreted factors, and mRNA profiling. The in vivo activity of EM-C was evaluated using a subcutaneous tumor model in immunocompetent mice. Murine EM-C were administered to tumor-bearing mice, and their ability to modulate the TME was monitored via immunophenotyping, secretome analysis, and single cell transcriptomics. To demonstrate modularity of the EM-C platform, additional SR were designed to convert TGFβ into interferon or toll-like receptor signals. Results: EM-C efficiently sequestered IL10 or TGFβ and upregulated pro-inflammatory markers, cytokines, and pathways in a dose-dependent manner in vitro. EM-C administered to tumor-bearing mice remodeled the TME immune compartment by increasing the abundance of CD8 T cells and reducing the presence of immunosuppressive Tregs. EM-C furthermore augmented the cytokine/chemokine profile of the TME in a manner that correlated with anti-tumor response. TME modulation by EM-C improved tumor control, as compared to non-engineered macrophages, and had additive efficacy with checkpoint blockade. Conclusion: We present a versatile immunotherapy platform that harnesses macrophages as “living converters” to locally augment inflammation in solid tumors. EM-C exhibit a modular ability to locally convert IL10 or TGFβ into pro-inflammatory signals without systemic cytokine antagonism. The EM-C platform enables development of target antigen-agnostic myeloid cell immunotherapies for overcoming immunosuppression in diverse solid tumors. Citation Format: Chris Sloas, Silvia Beghi, Yuhao Huangfu, Rehman Qureshi, Benjamin Schott, Michael Ball, Daniel Blumenthal, Thomas Condamine, Michael Klichinsky, Yumi Ohtani. Macrophages expressing synthetic cytokine receptors reverse IL10-mediated immunosuppression within solid tumors and promote adaptive immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5249.