Targeting Tumor Metabolism to Enhance the Effectiveness of Antitumor Immune Response in the Treatment of Breast Cancer

Abstract : It has been well established that tumor cells escape immune detection through immunosuppressive networks and is one of the hallmarks of cancer. Down-regulation of surface antigen is one of the immunosuppressive mechanisms that enable cancer cells to escape immune detection. Among several antigens, shedding or cleavage of MIC [MHC class I Chain-related]-A or MIC-B surface antigens is frequently witnessed in cancer cells. Shedding of MICA and/ or MICB has been implicated in tumor progression and immune evasion. Since MICA/B shedding is an energy-dependent process, we hypothesized that targeting energy metabolism of cancer cells could delay or prevent the shedding process resulting in an increased expression of MICA/ B and better immune detection. This will enable us to enhance the antitumor immune-response. Data from the current research investigation demonstrate that human breast cancer cells pre-treated with low, non-toxic dose of the glycolytic inhibitor, 3-bromopyruvate (3-BrPA) show a better response to antitumor immunotherapy. One of the major implications of the current finding is that at low, non-cytotoxic dose antiglycolytic agent, 3-BrPA induces minimal perturbation of metabolism which is sufficient to block the shedding or cleavage of MICA and/ or MICB. The outcome of our study suggests that antiglycolytic pre-treatment sensitizes breast cancer cells to enhance the effectiveness of immunotherapeutics in the treatment of human breast cancer.