PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy

Abstract

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

Keywords: Adverse effect; Biomarker; Combination therapy; Cost-effectiveness; Drug resistance; Gastrointestinal cancer; Immune checkpoint blockade; PD-1/PD-L blockade; Precision immunotherapy; Treatment evaluation.

Fig. 1

PD-1/PD-L pathway and therapeutic targeting. PD-1 contains an extracellular domain, transmembrane region, and cytoplasmic tail with ITIM and ITSM. During T cell activation through TCR crosslinking with antigen presented by MHC, PD-L1, and PD-L2 expressed on cancer cells downregulate T cell activity by binding to PD-1, unless blocked by anti-PD-1/PD-L1/PD-L2. Red arrows indicate inhibitory signals, and green lines indicate stimulatory signals

Fig. 2

The precision immunotherapy paradigm. GI cancers (star) escape the host immune response through the PD-1/PD-L pathway. Although the emergence of PD-1/PD-L blockade has renewed hope in immunotherapy, the response to PD-1/PD-L blockade is not as high as expected. The path toward precision immunology to improve efficiency includes six particularly important steps. The initial step in this process is to identify the population suitable for medication at the time of diagnosis for precision therapy. Once the drug is administered at the optimal time, the patient’s physical condition should be closely monitored, and side effects caused by the drug should be recognized in a timely manner. Concurrently, the efficacy of the drug should be properly evaluated. Upon disease progression, attempts should be made to overcome drug resistance to maintain efficacy. In addition, there is a need to improve the cost-effectiveness ratio to benefit more people. Through these efforts, precision immunotherapy of PD-1/PD-L blockade will become a reality