| Autor: |
Li, Fangda, Yang, Zaofeng, Savage, Thomas M., Vincent, Rosa L., de los Santos-Alexis, Kenia, Ahn, Alexander, Rouanne, Mathieu, Mariuzza, Dylan L., Danino, Tal, Arpaia, Nicholas |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 100, p1-13, 13p |
| Abstrakt: |
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. Editor's summary: Engineering bacteria to release therapeutic candidates within tumors circumvents the severe toxicity associated with systemic delivery and is a promising strategy for immunotherapy. Li et al. engineered a strain of E. coli to express the cytokine IFN-γ within the tumor core (SLIC–IFN-γ). In mice, intratumoral injection of SLIC–IFN-γ promoted antitumor immunity by polarizing tumor-associated myeloid cells and activating cytotoxic T cells. Furthermore, SLIC–IFN-γ overcame primary resistance to PD-1 blockade by activating antigen-specific T cells and overcame acquired resistance by activating NK cells. Together, these findings suggest that SLIC–IFN-γ is an attractive therapeutic strategy to overcome resistance to PD-1 blockade. —Hannah Isles [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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