Immunotherapy in gastric cancer

Abstract

Gastric cancer is the second most common of cancer-related deaths worldwide. In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved, survival rates remain poor. Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer, prostate cancer and melanoma. Here, we provide an overview of concepts of modern cancer immunotherapy including the theory, current approaches, remaining hurdles to be overcome, and the future prospect of cancer immunotherapy in the treatment of gastric cancer. Adaptive cell therapies, cancer vaccines, gene therapies, monoclonal antibody therapies have all been used with some initial successes in gastric cancer. However, to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response. Here, we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy. We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment. We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells. Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being. Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright.

Keywords: Adoptive cell therapy; Antibody therapy; Cancer vaccine; Gastric cancer; Immune checkpoint; Immune escape; Predictive biomarker.

Figure 1

Cancer immunoediting phases. A: Phase 1: Elimination. Tumor cells are recognized by innate and adaptive immune cell and are destroyed before they can become a clinical malignancy. Modified after Dunn GP[69]; B: Phase 2: Equilibrium. If tumor cells are not destroyed in the elimination phase, the tumor may enter an equilibrium phase. Genetic change and/or resistant to immune detection occur in the equilibrium phrase and tumor cells are maintained chronically. Modified after Dunn GP[69]; C: Phase 3: Escape. The tumor microenvironment allows that tumor cells to grow and change to become poorly immunogenic. The tumor microenvironment becomes immunosuppressive. Modified after Dunn GP[69]. NK: Natural killer; PD: Programmed death; IFN: Interferon; IL: Interleukin.

Figure 2

Cancer immunotherapy. Immunological approaches to cancer therapy are based on use of cytotoxic immunocytes (cytokine induced killer cells, tumor infiltration cells, tumor antigen loaded dendritic cells), cancer vaccines, monoclonal antibodies. Therapeutic vaccines enhance pre-existing immunity and lead to a more robust antitumor immune response whereas monoclonal antibodies are used to inhibit critical molecules for tumor growth and survival. PD: Programmed death.