Genetically Engineered Probiotic ILimosilactobacillus reuteri/I Releasing IL-22 Modifies the Tumor Microenvironment, Enabling Irradiation in Ovarian Cancer

• Published in: Cancers Vol. 16; no. 3
• Main Authors: Hamade, Diala F, Epperly, Michael W, Fisher, Renee, Hou, Wen, Shields, Donna, van Pijkeren, Jan-Peter, Leibowitz, Brian J, Coffman, Lan G, Wang, Hong, Huq, M. Saiful, Huang, Ziyu, Rogers, Claude J, Vlad, Anda M, Greenberger, Joel S, Mukherjee, Amitava
• Format: Journal Article
• Language: English
• Published: MDPI AG 01.01.2024
• Subjects: Analysis; Cancer; Chemotherapy; Development and progression; Gene expression; Genes; Genetic engineering; Genetically modified organisms; Health aspects; Immunotherapy; Interleukins; Mice; Ovarian cancer; Radiation; Stem cells; T cells
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16030474

Ovarian cancer is the most lethal gynecological cancer worldwide, and there is an urgent need for a cure. Previously, we established that a second-generation probiotic expressing interleukin-22 (LR-IL-22) is a radiation mitigator, and now, we have assessed its effect in an ovarian cancer mouse model. LR-IL-22 treatment improved survival, upregulated PD-L1 protein expression on cancer cells, and recruited CD8+ T cells to tumors in whole-abdomen irradiated (WAI) mice. The addition of LR-IL-22 to a therapy regimen that includes WAI, chemotherapy, and immunotherapy can facilitate a safe and effective protocol to reduce tumor burden, increase overall survival, and improve the quality of life of an ovarian cancer patient. Despite recent advances in cancer therapy, ovarian cancer remains the most lethal gynecological cancer worldwide, making it crucial and of the utmost importance to establish novel therapeutic strategies. Adjuvant radiotherapy has been assessed historically, but its use was limited by intestinal toxicity. We recently established the role of Limosilactobacillus reuteri in releasing IL-22 (LR-IL-22) as an effective radiation mitigator, and we have now assessed its effect in an ovarian cancer mouse model. We hypothesized that an LR-IL-22 gavage would enable intestinal radioprotection by modifying the tumor microenvironment and, subsequently, improving overall survival in female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer. Herein, we report that the LR-IL-22 gavage not only improved overall survival in mice when combined with a PD-L1 inhibitor by inducing differential gene expression in irradiated stem cells but also induced PD-L1 protein expression in ovarian cancer cells and mobilized CD8+ T cells in whole abdomen irradiated mice. The addition of LR-IL-22 to a combined treatment modality with fractionated whole abdomen radiation (WAI) and systemic chemotherapy and immunotherapy regimens can facilitate a safe and effective protocol to reduce tumor burden, increase survival, and improve the quality of life of a locally advanced ovarian cancer patient.