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Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer
Max Heiduk, … , Lena Seifert, Adrian M. Seifert
Max Heiduk, … , Lena Seifert, Adrian M. Seifert
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e152761. https://doi.org/10.1172/jci.insight.152761.
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Clinical Medicine Immunology Oncology

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

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Abstract

BACKGROUND Pancreatic 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.METHODS We 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.RESULTS In 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.CONCLUSION Neoadjuvant 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.FUNDING This 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.

Authors

Max Heiduk, Ioana Plesca, Jessica Glück, Luise Müller, David Digomann, Charlotte Reiche, Janusz von Renesse, Rahel Decker, Christoph Kahlert, Ulrich Sommer, Daniela E. Aust, Marc Schmitz, Jürgen Weitz, Lena Seifert, Adrian M. Seifert

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Figure 4

Neoadjuvant chemotherapy decreases the proportion of functionally exhausted CD8+ T cells in PDAC.

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Neoadjuvant chemotherapy decreases the proportion of functionally exhaus...
t-SNE analysis based on intracellular cytokine expression of tumor-infiltrating CD8+ T cells from patients who were primary resected (PR) (n = 8) and patients who received NEO (n = 8). (A) t-SNE analysis of CD8+ T cells merged (left) and separated distribution from patients who were PR and patients who received NEO (right). (B) t-SNE expression of indicated cytokines. (C) FlowSOM clustering into 10 clusters (P1–P10). (D) Heatmap depicting mean fluorescence intensity for cytokine expression of each cluster (left), and bar graph showing the distribution of each cluster within PR and NEO CD8+ T cells (right). (E) Proportion of CD8+ T cells within indicated clusters (PR vs. NEO). Each point represents data from 1 patient. Data are shown as the mean ± SEM. Unpaired 2-tailed t test. *P < 0.05.

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