Bacteria colonization in tumor microenvironment creates a favorable niche for immunogenic chemotherapy

• Published in: EMBO molecular medicine Vol. 16; no. 2; pp. 416 - 428
• Main Authors: Lim, See-Khai, Lin, Wen-Ching, Huang, Sin-Wei, Pan, Yi-Chung, Hu, Che-Wei, Mou, Chung-Yuan, Hu, Che-Ming Jack, Mou, Kurt Yun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2024; Springer Nature
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Bacteria Cancer Therapy; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Differential Stress Resistance; EMBO03; EMBO19; EMBO23; Immunotherapy; Immunotherapy - methods; Mice; Molecular Medicine; Neoplasms - drug therapy; Oxaliplatin - therapeutic use; Oxaliplatin; TME Remodeling; T-Lymphocytes, Cytotoxic; Tumor Microenvironment; Oxaliplatin; TME Remodeling; Bacteria Cancer Therapy; Differential Stress Resistance; Immunotherapy
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-023-00022-w

The tumor microenvironment (TME) presents differential selective pressure (DSP) that favors the growth of cancer cells, and monovalent therapy is often inadequate in reversing the cancer cell dominance in the TME. In this work, we introduce bacteria as a foreign species to the TME and explore combinatorial treatment strategies to alter DSP for tumor eradication. We show that cancer-selective chemotherapeutic agents and fasting can provide a strong selection pressure against tumor growth in the presence of bacteria. Moreover, we show that an immunogenic drug (oxaliplatin), but not a non-immunogenic one (5-FU), synergizes with the bacteria to activate both the innate and adaptive immunity in the TME, resulting in complete tumor remission and a sustained anti-tumor immunological memory in mice. The combination of oxaliplatin and bacteria greatly enhances the co-stimulatory and antigen-presenting molecules on antigen-presenting cells, which in turn bridge the cytotoxic T cells for cancer-cell killing. Our findings indicate that rational combination of bacterial therapy and immunogenic chemotherapy can promote anticancer immunity against the immunosuppressive TME. Synopsis Oxaliplatin, an immunogenic chemotherapeutic synergizes with bacteria cancer therapy for tumor eradication. The synergy was mediated by the ability of the combinations to alter the pro-tumoral immune milieu and impose a strong differential selective pressure to outcompete the tumor cells. Bacteria monotherapy exhibits moderate anticancer efficacy due to its limited ability to outcompete tumor cells in the tumor microenvironment. The addition of chemotherapy acts as a selective factor against tumor survival and enhances the efficacy of bacteria cancer therapy. The addition of immunogenic chemotherapy with bacteria treatment significantly enhances tumor-infiltrating T cells and leads to a long-lasting tumor remission. Oxaliplatin, an immunogenic chemotherapeutic synergizes with bacteria cancer therapy for tumor eradication. The synergy was mediated by the ability of the combinations to alter the pro-tumoral immune milieu and impose a strong differential selective pressure to outcompete the tumor cells.