Circulated T-cell exhausted subtypes to predict response in PDAC patients.

Abstract

4173 Background: In-depth analysis of T-cell exhausted subsets in the circulation of Pancreatic Ductal Adenocarcinoma (PDAC) patients may provide insights into novel therapeutic options and predictive biomarkers. We performed a detailed immunophenotypic analysis for both early-stage (resectable) and metastatic (unresectable) PDAC patients. Additionally, different T-cell populations were correlated with clinical outcome. Methods: Fifty-five treatment naive PDAC patients, twenty-five of which had resectable disease, and ten healthy donors (HD) were enrolled. Peripheral Blood Mononuclear Cells (PBMCs) were isolated and stained with fluorochrome-conjugated monoclonal antibodies. Multicolor flow cytometry was performed to determine differences between T-cell populations and their correlation with clinical outcome. Results: Advanced disease patients that harbored high percentages of CD4 + PD-1 + T eff cells had longer PFS (median: 190 vs. 100 days, p:0.030) and OS (median: 250 vs. 170 days, p:0.041) while for early-stage patients high percentages of CD8 + PD-1 + T eff displayed longer DFS (median: 422 vs. 200 days, p:0.044) and OS (median: Und vs. Und days, p:0.041). For early-stage patients, high percentages of both CD4 + and CD8 + T-cells expressing PD-1 + TCF1 + (exhausted cells) were predictive for survival (CD3 + CD4 + PD-1 + TCF1 + : med. Und vs. 277 days, p:0.0041) and (CD3 + CD8 + PD-1 + TCF1 + : med. Und vs. 390 days, p:0.042). Additionally, expression levels of PD-1 (MFI levels) were substantially elevated in the PD-1 + TCF1 - subset for both early stage CD3 + CD4 + (p:0.026), CD3 + CD8 + (p: = 0.006) and advanced-stage, (p:0.0001 and p:0.045, respectively), implying that terminally exhausted (PD-1 + TCF1 - ) T-cells exhibit higher PD-1 expression than primarily exhausted (PD-1 + TCF1 + ). For advanced stage patients, high levels of CD57 + , a marker of terminally differentiated T-cells, in CD3 + CD8 + were associated with improved PFS (118 vs. 92 days, p:0.178)and OS(271 vs. 152 days, p: 0.019), CD3 + CD8 + PD-1 + TCF1 + ( PFS: med. 260 vs. 60 days, p = 0.0063 ; OS: 271 vs. 90 days, p: 0.003) and CD3 + CD8 + PD-1 + TCF1 - T-cells (PFS: med. 188 vs. 80 days, p = 0.0459 ; OS: 271 vs. 107 days, p = 0.0429). CD57 + T-cells were not correlated with response in early-stage patients. Conclusions: T-cell exhaustion represents ineffective immune response and in both early and advanced-stage PDAC may predict clinical outcome offering opportunities for innovative therapeutic options for this fatal disease.