Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma.

Abstract

Simple SummaryPancreatic cancer is deadly, and new treatments are urgently needed. Pancreatic cancer, in particular, effectively escapes the immune response, which is why drugs are developed that stimulate the immune system to remove the tumor. Here, we investigated potential drug targets, the checkpoint inhibitors IDO, VISTA, LAG3, and TIM3. If these checkpoint molecules are associated with poor survival, inhibitory drugs could improve survival. We analyzed 153 pancreatic cancer patients and assessed the expression of checkpoint molecules using immunohistochemistry on tissue microarrays. More than two immune checkpoint molecules were not co-expressed in relevant numbers at the same time. Patients with IDO-expressing tumors had better survival. VISTA, LAG3, and TIM3 expression did not correlate with survival. We expect that immune checkpoint inhibitors against VISTA, LAG3, and TIM3 will not improve patient survival. Our findings complement the picture of pancreatic cancer as highly inaccessible by immune checkpoint inhibitors.Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.