PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer

Seifert, Adrian M.; Eymer, Annabel; Heiduk, Max; Wehner, Rebekka; Tunger, Antje; Renesse, Janusz von; Decker, Rahel; Aust, Daniela E.; Welsch, Thilo; Reißfelder, Christoph; Weitz, Jürgen; Schmitz, Marc; Seifert, Lena

doi:10.3390/cancers12102756

Cited by 19 publications

(18 citation statements)

References 42 publications

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“…In line with our data, LAG-3 expression may be a potential mechanism of immune evasion in PDAC, especially since in non-small cell lung carcinoma (NSCLC) prominent LAG-3 expression by T cells was associated with insensitivity to PD-1 blockade [ 39 ]. Recently, we have shown a relevant role for PD-1 in the immune suppressive network of T cells from PDAC-draining lymph nodes [ 40 ]. Here, we observed prolonged DFS in PDAC patients with an increased density of PD-1 expressing T cells, suggesting a double-edged role of PD-1+ T cells.…”

Section: Discussionmentioning

confidence: 99%

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

Seifert

Plesca

Müller

et al. 2021

Cancers

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T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8+ and Th1-polarized CD4+ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3+ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.

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Section: Discussionmentioning

confidence: 99%

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

Seifert

Plesca

Müller

et al. 2021

Cancers

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“…In contrast, we have observed that a high infiltration of LAG-3 + T cells is a negative independent prognostic factor for DFS [ 54 ]. In addition, an increased density of Tregs was linked to worse clinical outcome, while a high frequency of intratumoral PD-1 + Tregs was correlated with lymph node metastasis [ 53 , 58 , 59 ]. When investigating macrophages as another major component of the tumor immune contexture, it has been shown that they mainly polarize toward an M2 phenotype in PDAC [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of Tumor-Infiltrating Conventional and Plasmacytoid Dendritic Cells in Pancreatic Ductal Adenocarcinoma

Plesca

Benešová

Beer

et al. 2022

Cancers

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Dendritic cells (DCs) play a key role in the orchestration of antitumor immunity. Activated DCs efficiently enhance antitumor effects mediated by natural killer cells and T lymphocytes. Conversely, tolerogenic DCs essentially contribute to an immunosuppressive tumor microenvironment. Thus, DCs can profoundly influence tumor progression and clinical outcome of tumor patients. To gain novel insights into the role of human DCs in pancreatic ductal adenocarcinoma (PDAC), we explored the frequency, spatial organization, and clinical significance of conventional DCs type 1 (cDC1s) and type 2 (cDC2s) and plasmacytoid DCs (pDCs) in primary PDAC tissues. A higher density of whole tumor area (WTA)- and tumor stroma (TS)-infiltrating cDC1s was significantly associated with better disease-free survival (DFS). In addition, an increased frequency of intraepithelial tumor-infiltrating cDC2s was linked to better DFS and overall survival (OS). Furthermore, an increased density of WTA- and TS-infiltrating pDCs tended to improve DFS. Moreover, a higher frequency of WTA- and TS-infiltrating cDC1s and pDCs emerged as an independent prognostic factor for better DFS and OS. These findings indicate that tumor-infiltrating DCs can significantly influence the clinical outcome of PDAC patients and may contribute to the design of novel treatment options that target PDAC-infiltrating DCs.

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“…In addition, a recent study suggested that CD4 + T cells, as pivotal regulators of PDL1 levels, determined the immune responsiveness to PD1-based immune checkpoint therapy in OSCC patients [26]. The expression of the inhibitory receptor PD1 through lymph node and tumor-in ltrating regulatory T cells have been shown to be correlated with lymph node metastasis in pancreatic ductal adenocarcinoma [27]. The presence of metastatic neck nodes and tumor recurrence is associated with poor prognoses [28; 29].…”

Section: Discussionmentioning

confidence: 99%

Increased Levels of PD1 and Glycolysis in CD4+ T Cells Promote Lymph Node Metastasis in Oral Squamous Cell Carcinoma Patients

Han

Zhang

et al. 2022

Preprint

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Background: Cervical lymph node metastasis is one of the poorest prognostic factors in oral squamous cell carcinoma (OSCC). Activated immune cells and cancer cells generally have metabolic similarities in tumor microenvironment. However, it is unknown whether abnormal glycolysis in T cells could facilitate metastatic lymph nodes in patients with OSCC. Methods: Flow cytometry and immunofluorescence staining were used to analyze the differences in CD4+ PD1+ T cells between metastatic and negative lymph nodes. RT-PCR was performed to detail the expression of immune checkpoints and glycolysis-related enzymes in metastatic and negative lymph nodes. Kruskal-Wallis, Mann-Whitney, or nonparametric paired tests (i.e., the Wilcoxon matched paired test) were used to analyze the non-parametric distribution of the samples. Results: The frequency of CD4+ T cells decreased in the metastatic lymph nodes (p = 0.0019). Immune checkpoints (PD1, PDL1, and CTLA4) of CD4+ T cells were detected in metastatic (LN+) and paired negative lymph nodes (LN-) of OSCC patients. The PD1 expression of LN+ increased markedly compared to that of LN- (p = 0.0205). Similarly, the PD1 of CD4+ T cells in LN+ increased significantly compared to that of LN-. Glycolysis-related enzyme levels in CD4+ T cells from LN+ were dramatically higher than those in LN-. Moreover, PD1 and Hk2 expressions in CD4+ T cells increased in metastatic lymph nodes of OSCC patients with prior surgical treatment compared to those without. Conclusions: These findings suggest that increased PD1 and glycolysis in CD4+ T cells may serve as pivotal regulators of OSCC metastatic lymph nodes, which are closely associated with elevated glycolysis.

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PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer

Cited by 19 publications

References 42 publications

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer

Clinical Significance of Tumor-Infiltrating Conventional and Plasmacytoid Dendritic Cells in Pancreatic Ductal Adenocarcinoma

Increased Levels of PD1 and Glycolysis in CD4+ T Cells Promote Lymph Node Metastasis in Oral Squamous Cell Carcinoma Patients

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