The role of intratumoral gamma-delta T cells in pancreatic cancer – characterization, interaction and modulation
Final Report Abstract
The goal of the project was to phenotypically and functionally investigate γδT-cells in pancreatic ductal adenocarcinoma (PDAC) and analyze their impact on the tumor microenvironment as well as on chemotherapy and immunotherapies, in order to develop new therapeutic approaches. Initially, γδT-cells were investigated in 70 PDAC patient samples and normal tissues. It was found that γδT-cells were primarily localized in the tumor stroma and near pancreatic stellate cells (PSCs). Their infiltration was not associated with tumor spread or lymph node metastases, but high expression of the γδT-cell-associated gene TRGC2 correlated with the expression of extracellular matrix genes (ECM). In vitro, it was shown that γδT-cells enhanced the IL-6 production by PSCs, which identified the interaction between γδT-cells and PSCs as a potential target for therapeutic interventions in PDAC. Additionally, γδT-cells were analyzed in tumor tissue and peripheral blood from over 150 PDAC patients using flow cytometry. It was observed that γδT-cells, especially regulatory T-cells and conventional T-cells, highly expressed the inhibitory immune receptor TIGIT. The PD-1⁺TIGIT⁻ T-cells expressed pro-inflammatory cytokines and markers of tumor reactivity and were associated with better clinical outcomes. In contrast, TIGIT expression was associated with anti-inflammatory and exhausted phenotypes. An increased presence of PD-1⁺TIGIT⁻ T-cells in the tumor tissue was linked to better overall survival (OS), while high TIGIT expression in blood T-cells was associated with a poorer prognosis. Another aspect of the study was the investigation of the effects of neoadjuvant chemotherapy on T-cell infiltration in PDAC. It was found that chemotherapy increased T-cell density in the ductal region of the tumor. In particular, the frequency of conventional CD4⁺ T-cells (Tconv) increased, while the proportion of regulatory T-cells (Treg) in the tumor microenvironment decreased after treatment. Additionally, there was an increase in the production of proinflammatory cytokines such as TNFα and IL-2, while IL-4 and IL-10 were reduced. These changes in the T-cell profile suggest that neoadjuvant chemotherapy influences the tumor microenvironment towards a pro-inflammatory profile. This could increase the potential for combined treatment approaches with T-cell-based immunotherapies in neoadjuvant regimens for PDAC. Based on the previous analyses, the role of the TIGIT axis in PDAC is being further investigated, with Nectin-4 identified as a ligand exclusively expressed on tumor cells. A multicenter, prospectively randomized study is currently being initiated to evaluate the efficacy of Enfortumab Vedotin compared to neoadjuvant standard chemotherapy in patients with locally advanced PDAC.
Publications
-
Gamma-delta T cells stimulate IL-6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma. Journal of Cancer Research and Clinical Oncology, 146(12), 3233-3240.
Seifert, Adrian M.; List, Julian; Heiduk, Max; Decker, Rahel; von Renesse, Janusz; Meinecke, Ann-Christin; Aust, Daniela E.; Welsch, Thilo; Weitz, Jürgen & Seifert, Lena
-
LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer. Cancers, 13(6), 1297.
Seifert, Lena; Plesca, Ioana; Müller, Luise; Sommer, Ulrich; Heiduk, Max; von Renesse, Janusz; Digomann, David; Glück, Jessica; Klimova, Anna; Weitz, Jürgen; Schmitz, Marc & Seifert, Adrian M.
-
Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer. JCI Insight, 7(22).
Heiduk, Max; Plesca, Ioana; Glück, Jessica; Müller, Luise; Digomann, David; Reiche, Charlotte; von Renesse, Janusz; Decker, Rahel; Kahlert, Christoph; Sommer, Ulrich; Aust, Daniela E.; Schmitz, Marc; Weitz, Jürgen; Seifert, Lena & Seifert, Adrian M.
-
Neoadjuvant chemotherapy is associated with enhanced pro-inflammatory functionality of intratumoral CD4+ T cells in pancreatic cancer, Tumor Immunology Meets Oncology (TIMO) XVI, Halle
Lena Seifert
-
Die Expression von TIGIT identifiziert T-Zellpopulationen im Pankreaskarzinom mit prognostischer Relevanz und spezifischer Funktion, Viszeralmedizin, Hamburg
Lena Seifert
-
Inhibitory receptor expression delineates T cell populations with distinct function in pancreatic cancer, UEG Week, Kopenhagen
Lena Seifert
-
Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer, 42. Jahrestagung des Deutschen Pankreasclubs, München
Lena Seifert
-
PD-1 and TIGIT delineate T cell populations with different functional and prognostic impact in pancreatic cancer, Tumor Immunology Meets Oncology (TIMO) XVII, Halle
Lena Seifert
-
PD-1 and TIGIT expression delineate distinct functional T cell subsets with prognostic relevance in pancreatic cancer, CIMT Annual Meeting, Mainz
Lena Seifert
-
The TIGIT ligand nectin-4 but not CD155 is associated with reduced survival and impaired immune infiltration in pancreatic cancer, CRI-ENCI-AACR International Cancer Immunotherapy Conference, Mailand
Lena Seifert
-
TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer. Clinical Cancer Research, 29(14), 2638-2650.
Heiduk, Max; Klimova, Anna; Reiche, Charlotte; Digomann, David; Beer, Carolin; Aust, Daniela E.; Distler, Marius; Weitz, Jürgen; Seifert, Adrian M. & Seifert, Lena
-
Comprehensive analysis of the TIGIT-axis identifies the immunological and clinical significance of Nectin-4 in pancreatic cancer, 43. Jahrestagung des Deutschen Pankreasclubs, Bonn
Lena Seifert
