Li et al. engineered E. Coli Nissle to produce IFNγ with a synchronized integrated lysing circuit (SLIC-IFNγ), where at high density, the bacteria lyse and release IFNγ in recurring cycles. Relative to controls, i.t. injection of SLIC-IFNγ increased intratumoral IFNγ, TNFα+ and tumor- specific T cells, and antitumor efficacy, and also controlled contralateral tumors. In B2M- or JAK-deficient tumor models, or when injected i.v., SLIC-IFNγ remained effective and was further improved alongside anti-PD-1. Efficacy of i.t. SLIC-IFNγ in primary B2M-/- tumors was dependent on NK cells, and in contralateral WT tumors, relied on systemic T cell responses.
Contributed by Alex Najibi
ABSTRACT: Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ-producing bacteria was sufficient to drive systemic tumor antigen-specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3-CD4+ and CD8+ T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ-producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.
Author Info: (1) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (2) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (3) De
Author Info: (1) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (2) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (3) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (4) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (5) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (6) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (7) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (8) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. (9) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. Data Science Institute, Columbia University, New York, NY, USA. (10) Department of Microbiology and Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
