The spatial coexistence of TIGIT/CD155 defines poorer survival and resistance to adjuvant chemotherapy in pancreatic ductal adenocarcinoma

Background: Targeting emerging T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT)/CD155 axis shows promise for restoring anti-tumor immunity, but its immune phenotypes and prognostic significance in a large cohort of pancreatic ductal adenocarcinoma (PDAC) are limited. Methods: Three seven-color multispectral panels were rationally designed to investigate the protein expression, immune-microenvironmental feature, prognostic value, and the response to adjuvant chemotherapy of TIGIT/CD155 in 272 PDAC specimens using multiplex immunohistochemistry. Results: We revealed low immunogenicity and high heterogeneity of the PDAC immune microenvironment featured by abundant CD3(+) T cells and CD68(+) macrophages and low infiltration of activated cytotoxic T lymphocytes. TIGIT and CD155 were highly expressed in PDAC tissues compared to paracancerous tissues. Tumor-infiltrating lymphocytes expressing TIGIT were correlated with high densities of CD45RO(+) T cells; TIGTI(+)CD8(+) T cells were associated with high infiltration of CD3(+)CD45RO(+)FOXP3(+). CD155(+)CK(+) were significantly related to high densities of CD3(+) and CD3(+)CD8(+)CD45RO(+) T cells. High positive rates for TIGIT in TCs, CD8(+) T cells, and CD155 in macrophages were correlated with poor progression-free and disease-specific survival, respectively, and their clinical significance was correlated with PD-L1 status. Notably, spatial co-existence of TIGIT(+)CK(+) or TIGIT(+)CD8(+) and CD155(+)CD68(+) indicated poor survival and resistance to adjuvant chemotherapy response in patients with PDAC. Conclusion: Our findings suggest that targeting TIGIT/CD155 immunosuppressive axis may guide patient stratification and improve the clinical outcome of PDAC.