Pankreas Kanserinde Nectin-2 Ekspresyonu ile Sitotoksik T Hücre Fonksiyonları Arasındaki İlişki

Abstract

Checkpoint inhibitors such as anti-CTLA-4, anti-PD1 and anti-PDL-1 are used in the treatment of various cancers. However, they cannot be used in pancreatic cancer due to the lack of PDL-1 expression. Other checkpoint molecules include TIGIT family members TIGIT, CD96, DNAM-1, PVRIG. The ligands of these receptors are polio virus receptor (PVR) and Nectin family members. Nectin-2 acts as a ligand for these receptors and its role in pancreatic cancer is not fully known. The aim of this thesis is to cross-sectionally analyze the expression levels of Nectin-2 and its ligand receptors TIGIT, PVRIG, DNAM-1. In our study, the expressions of Nectin-2, CD8, TIGIT, PVRIG, DNAM-1, PD-1, PD-L1, LAG3, TIM3, VISTA, KI-67 molecules were examined in tumor tissues of 131 patients diagnosed with pancreatic cancer. Nectin-2 was not expressed in undiseased pancreatic tissue, whereas it was expressed in 30.5% of tumor tissues. PD-1 and PD-L1 expression was not observed in any of the patients. In the group with low density of CD8 TILs, the number of patients with negative Nectin-2 expression was higher than the number of patients with positive expression. In 32 patients with positive expression of Nectin-2, KI-67 proliferation marker was highly expressed. In the patient group where Nectin-2 was not expressed, the number of patients showing TIGIT expression increased. PVRIG and DNAM-1 were also not observed in the absence of Nectin-2. Patients without Nectin-2 expression had a higher number of patients without LAG3 and TIM3 expression. Nectin-2 was observed to be significantly underexpressed in stages 3 and 4 of pancreatic cancer. When the relationship between TIGIT receptor and the expression of PVRIG and DNAM-1 molecules was analyzed, a negative relationship was found and it was statistically significant. The median tumor size was 4 cm in the PVRIG positive staining group and 3 cm in the negative expression group. PVRIG and DNAM-1 positivity was more expressed in stage 2 than in stage I. There was a positive correlation between LAG3 expression and TIM3 expression. It was also observed that the presence of lymphovascular invasion increased in patients with positive LAG3 and VISTA expression. Lenf node metastasis was also significantly increased in patients with positive LAG3, TIM3 and VISTA expressions. Expression levels of VISTA molecule showed a significant difference in clinical stage 3. These data suggest that there may be a close relationship between Nectin-2 expression and the function of CD8+ cells. Further studies are needed to explain the mechanism of this relationship and to demonstrate the targetability of Nectin-2.