Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer

作者：Sarah Bazargan, Brittany Bunch, Awino Maureiq E. Ojwang’, Jamie Blauvelt, Annick Landin, Johannes Ali, Dominique Abrahams, Cheryl A. Cox, Amy M. Hall, Matthew Beatty, Michael Poch, Katarzyna A. Rejniak, Shari Pilon‐Thomas · 发表于：Frontiers in Immunology · 年份：2023 · DOI：10.3389/fimmu.2023.1275375 · 被引用次数：25 · 研究领域：Immune cells in cancer、CAR-T cell therapy research、Immune responses and vaccinations

Background: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Methods: Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. Results: In comparison to healthy donors, urine specimen from bladder cancer patients sh...