Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer.

Autor: Heiduk M; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany., Plesca I; Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Glück J; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Müller L; Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Digomann D; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Reiche C; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., von Renesse J; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Decker R; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Kahlert C; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.; German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany., Sommer U; Institute of Pathology, Faculty of Medicine Carl Gustav Carus, and., Aust DE; Institute of Pathology, Faculty of Medicine Carl Gustav Carus, and.; National Center for Tumor Diseases, Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Schmitz M; National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.; Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany., Weitz J; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.; German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany., Seifert L; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.; German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany., Seifert AM; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.; National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.; German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2022 Nov 22; Vol. 7 (22). Date of Electronic Publication: 2022 Nov 22.
DOI: 10.1172/jci.insight.152761
Abstrakt: BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%-40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODSWe performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTSIn human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSIONNeoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDINGThis work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.
Databáze: MEDLINE
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