TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer

Abstract

Purpose: Immunotherapy has led to a fundamental shift in the treatment of several cancers. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) is limited. Understanding the expression of inhibitory immune checkpoint receptors (ICR) by intratumoral T cells may help to unravel their involvement in insufficient T cell-mediated antitumor immunity. Experimental Design: Using multicolor flow cytometry, we analyzed circulating and intratumoral T cells from blood (n = 144) and matched tumor samples (n = 107) of PDAC patients. We determined the expression of PD-1 and TIGIT by CD8+ T cells, conventional CD4+ T cells (Tconv) and regulatory T cells (Treg) and their association with T cell differentiation, tumor reactivity, and cytokine expression. A comprehensive follow-up was used to determine their prognostic value. Results: Intratumoral T cells were characterized by increased PD-1 and TIGIT expression. Both markers delineated distinct T cell subpopulations. PD-1+TIGIT- T cells highly expressed proinflammatory cytokines and markers of tumor reactivity (CD39, CD103), whereas TIGIT expression was linked to antiinflammatory and exhausted phenotypes. In addition, the enhanced presence of intratumoral PD-1+TIGIT- Tconv was associated with improved clinical outcomes, while high ICR expression on blood T cells was a significant hazard for overall survival. Conclusions: Our results uncover the association between ICR expression and T cell functionality. PD-1 and TIGIT characterized intratumoral T cells with highly divergent phenotypes linked to clinical outcomes, further underscoring the relvance of TIGT for immunotherapeutic approaches in PDAC. The prognostic value of ICR expression in patient blood may be a valuable tool for patient stratification.

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…Additionally, TIGIT can competitively bind to CD226 or CD96 along with CD155 and CD112 in order to suppress the active signal received by T-cells [347]. Increased PD-1 and TIGIT expression were evident in intratumoral T cells [348]. Thus, to optimize the responses of CD8 + T cells against tumors, it is necessary to co-block the TIGIT and PD-1 inhibitory pathways due to their mechanistic convergence [349].…”