Current Status and Future Perspective of Immunotherapy in Gastrointestinal Cancers

Abstract

Gastrointestinal (GI) cancers represent a major public health problem worldwide. Due to the late detection and high heterogeneity of GI cancers, traditional treatments, including surgery, radiotherapy, chemotherapy, and targeted therapy, have shown limited effects, and the overall prognosis of these patients remains poor. Recently, immunotherapy, involving programmed cell death-1 (PD-1) and its ligand (PD-L1), has shown promising efficacy in several solid cancers and seems to have become a potential treatment option for GI cancers This review focuses on data on the development of immunotherapy-based clinical trials in esophageal cancer, gastric cancer, and colorectal cancer. The predictive biomarkers and combination strategies in clinical trials and translational medicine are also discussed. Finally, prospects for immunotherapy in the treatment of GI cancers are described. Although only a small proportion of patients with GI cancers respond to PD-1/PD-L1 blockade, we strongly believe that precision immunotherapy might improve the overall survival of many more GI cancer patients in the future.

Keywords: biomarkers; gastrointestinal cancer; immune checkpoint blockade; precision immunotherapy.

Graphical abstract

Figure 1

Predictive Biomarkers for Immune Checkpoint Inhibitors in GI Cancer. The current immunotherapeutic biomarkers in GI cancer were developed on the basis of the mechanism of antitumor immunity. Consideration of each step of the cancer immune cycle must be incorporated in the ongoing efforts of biomarker optimization in GI cancer.

Figure 2

Future Perspective of Immunotherapy. For precision immunotherapy, shown above, the following aspects could be focused upon, based on the tumor environment. (1) Identification of potential precise biomarkers. With the current understanding of cancer immunology, biomarkers could be identified in multi-omics, and combinational strategies taken into account to guide precision immuno-oncology. (2) Exploration of the precise combination strategies. Based on the complexity of TME, the different combination strategies of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and so forth that co-target the function of tumor-specific factors could be considered. (3) Identification of the timing of immunotherapy. Neoadjuvant therapy showed promising prevention of tumor relapse, even better than adjuvant therapy in some preclinical mouse models and clinical trials, providing a new option for patients. Therefore, it is necessary to confirm the appropriate timing of immunotherapy to obtain better efficacy. (4) Identification of the strategy to reverse acquired resistance. Acquired resistance to ICIs always discounts the efficiency of immunotherapy and remains a big challenge, so it is imperative to understand the mechanism of acquired resistance. The strategies that analyze the antigen presentation machinery, target mutation in IFN-γ signaling, block additional inhibitory checkpoints, increase neoantigen expression, decrease immunosuppressive cells or factors, increase T cell infiltration, and so forth could be explored to reverse acquired resistance.