Immunogenic Modulation of Prostate Cancer to Enhance IL‐27 Immunotherapy Efficacy

One of the most common metastatic sites for advanced prostate cancer is bone tissue. Treatment options for bone‐metastatic prostate cancer are currently limited, with immunogenic modulation (IMO) emerging as a possible therapeutic option. IMO involves modulation of cancer cell phenotype by sub‐lethal doses of chemotherapy, making them more susceptible to an immune attack. Such modulation can improve the efficacy of immunotherapeutic agents such as interleukin‐27 (IL‐27). By utilizing the immune system to eliminate tumors, one can effectively reduce chemotherapy toxicity and the associated side‐effects. Moreover, an IMO approach may enable one to treat tumors unresponsive or resistant to chemotherapy. Our main goals for this project are to investigate if prostate cancer cells respond to sub‐lethal doses of chemotherapy drugs through IMO and if IL‐27 immunotherapy can enhance tumor cell killing following IMO. To achieve these goals, we developed a functional assay utilizing immune‐killing in vitro with human prostate cancer cell lines following exposure to varying sub‐lethal concentrations of chemotherapeutics (docetaxel and cabozantinib). Prostate cancer cells co‐cultured with peripheral blood mononuclear cells (PBMCs) and IL‐27 were imaged for 72 h using an Incucyte live‐cell analysis system. A caspase 3/7 green apoptosis reagent was used to quantify apoptosis over time. Immune‐killing is currently being investigated for two human prostate cancer cell lines – PC3 (human prostate cancer adenocarcinoma) and C4‐2B (derivative of human prostatic carcinoma LNCaP). Studies in vivo to profile tumor‐infiltrating immune effectors will help characterize the associated immune response and examine whether chemotherapy and immunotherapy (IL‐27) administered via gene delivery methods can act in synergy to enhance the anti‐tumor immune response while promoting bone repair. We anticipate that such combinational therapy will open new avenues for treating bone‐metastatic prostate cancer while reducing chemotherapy‐associated toxicity and promoting healthy musculoskeletal tissue repair.Support or Funding InformationR01CA196947