Development of combinatorial immunotherapy for patients with advanced gastric cancer from the perspective of immunosuppressive mechanisms in the tumor microenvironment

Combinatorial immunotherapy using anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) is being developed to overcome the limited efficacy of monotherapy with anti-PD-1 mAb for patients with advanced gastric cancer (GC). Anti-PD-1 mAb exhibits clinical efficacy by enhancing the function of cytotoxic T lymphocyte (CTL) through the inhibition of the PD-1 pathway;however, there are various immunosuppressive mechanisms that inhibit CTL function, as well as the PD-1 pathway in the tumor microenvironment (TME). Immune suppressive cells and expression of the inhibitory immune checkpoint molecules are included as main inhibitory mechanisms against CTL in the TME. On the other hand, increasing the number of CTLs enhances the efficacy of anti-PD-1 mAb, and immunogenic tumor cell death (ICD) is crucial to induce CTL through the activation of the cancer immunity cycle. In the present review, we discuss the therapeutic potential of developing combinatorial immunotherapy focusing on the inhibitory immune checkpoint molecules and immune suppressive cells in the TME, as well as on the ICD induced by radiotherapy for patients with advanced GC.