Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis

Abstract

To increase the effectiveness of anticancer therapy based on immune checkpoint (IC) inhibition, some ICs are being investigated in addition to those used in clinic. We reviewed data on the relationship between PD-L1, B7-H3, B7-H4, IDO1, Galectin-3 and -9, CEACAM1, CD155, Siglec-15 and ADAM17 expression with cancer development in complex with the results of clinical trials on their inhibition. Increased expression of the most studied ICs—PD-L1, B7-H3, and B7-H4—is associated with poor survival; their inhibition is clinically significant. Expression of IDO1, CD155, and ADAM17 is also associated with poor survival, including gastric cancer (GC). The available data indicate that CD155 and ADAM17 are promising targets for immune therapy. However, the clinical trials of anti-IDO1 antibodies have been unsatisfactory. Expression of Galectin-3 and -9, CEACAM1 and Siglec-15 demonstrates a contradictory relationship with patient survival. The lack of satisfactory results of these IC inhibitor clinical trials additionally indicates the complex nature of their functioning. In conclusion, in many cases it is important to analyze the expression of other participants of the immune response besides target IC. The PD-L1, B7-H3, B7-H4, IDO1 and ADAM17 may be considered as candidates for prognosis markers for GC patient survival.

Exploration of the Tumor Immune Landscape and Identification of Two Novel Immunotherapy-Related Genes for Epstein-Barr virus-associated Gastric Carcinoma via Integrated Bioinformatics Analysis

“…The ICPs include Siglec-15, CTLA4, LAG3, PD-1, PD-L1, TIGIT, PD-L2, and HAVCR2. Siglecs are novel promising targets for GC immunotherapy, among which Siglec-15 has been widely studied ( 23 ). A previous study has explored the expression of Siglec-15 in GC tissues and evaluated its clinical value ( 24 ).…”

The Features of Checkpoint Receptor—Ligand Interaction in Cancer and the Therapeutic Effectiveness of Their Inhibition

“…The situation is similar to that of TIM-3. We observed similar relationships when analyzing IC ligands—most often, those ligands that showed a good relationship with clinical characteristics were effective as targets for anticancer therapy [ 179 ]. In this regard, it should be noted that the expression of TIGIT and BTLA correlates well with clinical characteristics.…”

“…The relationship of VISTA expression with the clinical characteristics of the tumor is contradictory, and the results of antitumor activity in the case of VISTA inhibition are inconsistent. Such results are also characteristic of some other immune checkpoints that function under conditions of multiple interactions [ 179 ]. A deeper understanding of VISTA’s mechanisms of action in cancer is needed for the successful therapeutic application of VISTA in cancer immunotherapy.…”

B7 family protein glycosylation: Promising novel targets in tumor treatment

“…However, the B7-H4 protein is highly expressed in human tumors and is associated with the clinicopathological features of patients (157). The expression of B7-H4 in gastric (169,170), breast (171,172), lung (145), prostate (173), pancreatic (174), bladder (175), colorectal (176), ovarian (177), renal (178), urothelial (179), esophageal (180), and gallbladder (181) cancers is associated with tumor size, primary tumor grade, TNM stage, low survival rate, drug…”

“…However, the B7-H4 protein is highly expressed in human tumors and is associated with the clinicopathological features of patients ( 157 ). The expression of B7-H4 in gastric ( 169 , 170 ), breast ( 171 , 172 ), lung ( 145 ), prostate ( 173 ), pancreatic ( 174 ), bladder ( 175 ), colorectal ( 176 ), ovarian ( 177 ), renal ( 178 ), urothelial ( 179 ), esophageal ( 180 ), and gallbladder ( 181 ) cancers is associated with tumor size, primary tumor grade, TNM stage, low survival rate, drug resistance and a decreased number of tumor-infiltrating T cells. B7-H4 inhibits the proliferation, cell cycle progression and cytokine production of CD4 + /CD8 + T cells ( 168 , 182 ), attenuates the inflammatory response, and enables tumor cells to evade the immune system ( 132 , 183 ).…”