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Purpose: Defining the phenotypic characteristics of CD8+T cell subsets in gastric cancer (GC) can help remodel the immune microenvironment of the tumor, thereby improving patient prognosis. CD226 has recently been shown to regulate the activity of CD8+T cell in several malignancies. However, the clinical relevance of CD226+CD8+T cells in GC remains unclear. Methods: Fudan University Shanghai Cancer Center (FUSCC) cohort (n = 316), The Cancer Genome Atlas (TCGA) cohort (n = 407), KUGH/KUCM cohort (n = 202), and Asian Cancer Research Group (ACRG) cohort (n = 300) were included in prognosis and response to adjuvant chemotherapy (ACT) analyses. Flow cytometry and multiplex immunostaining were used to characterize CD226+CD8+T cells. Results: CD226+CD8+T cells predicted favorable outcomes in patients undergoing curative resection for GC. GC patients with high CD226+CD8+T cell infiltration benefitted more from adjuvant chemotherapy. CD155 is upregulated in GC tissues and is associated with decreased intra-tumoral CD226+CD8+T cell infiltration. The combination of intra-tumoral CD226+CD8+T cells and CD155 is a strong prognostic predictor in patients with GC. Conclusion: CD226+CD8+T cells may represent a novel therapeutic target and a useful marker of prognosis and therapeutic response in patients with GC. [ABSTRACT FROM AUTHOR]

Purpose: Apatinib, an antiangiogenic drug, has shown beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. Methods: Immunocompetent mice with subcutaneous MFC tumors grown were given a combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. Results: Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. Conclusion: Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC. [ABSTRACT FROM AUTHOR]