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Flow cytometric analysis of the T cell subtype proportions. The proportions of CD4+ T cells, CD8+ T cells and Tregs in PBMCs and in pancreatic tissue lymphocytes or tumor-infiltrating lymphocytes from healthy control and PDA patients were analyzed via FCM. (A) Lymphocyte dot plots. The gate for lymphocytes is indicated. (B) CD4+ and CD8+ T cells were defined based on CD4+CD8− and CD8+CD4− gating of CD3+ T cells. (C) Dot plots of Foxp3+CD25+ (Treg) cells based on the gating of CD4+ T cells. (D) Statistical analyses of the CD8+ T cell, CD4+ T cell and Treg percentages in the indicated groups. C-PBMCs, control peripheral blood mononuclear cells; PDA-PBMCs, PBMCs of PDA; C-PTL, control pancreatic tissue lymphocytes; PDA-TIL, tumor-infiltrating lymphocytes of PDA. Comparisons between the two groups were assessed using Student's t test. NS, not significant; *** P<0.001.
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CD4+CD25+Foxp3+ regulatory T cells (Tregs) can inhibit cytotoxic responses. Though several studies have analyzed Treg frequency in the peripheral blood mononuclear cells (PBMCs) of pancreatic ductal adenocarcinoma (PDA) patients using flow cytometry (FCM), few studies have examined how intratumoral Tregs might contribute to immunosuppression in the...
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Systemic and local chronic inflammation might enhance the risk of pancreatic ductal adenocarcinoma (PDAC), and PDAC-associated inflammatory infiltrate in the tumor microenvironment concurs in enhancing tumor growth and metastasis. Inflammation is closely correlated with immunity, the same immune cell populations contributing to both inflammation an...
A growing body of evidence suggests that BRAF-inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present studies aimed to define the immunological basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the...
Citations
... Transforming growth factor-beta and IL-10 produced by Treg cells have been demonstrated to suppress immune responses [110]. An elevated abundance of tumor-infiltrating Treg cells impairs the antitumor activity of CD8+ T cells and portends a worse prognosis in PDAC [111]. High-risk individuals also owned a greater abundance of T2 cells compared to low-risk individuals in this study. ...
Background. Pyroptosis has a dual function in malignant tumor progression and management. The action of pyroptosis-related genes (PRGs) in pancreatic cancer (PC), however, remains uncertain. Methods. Differential expression analyses of 57 PRGs were conducted in the TCGA TARGET GTEx dataset. The candidate genes were determined using LASSO Cox regression and random forest analyses. A risk model was developed with the TCGA dataset and validated with the ICGC dataset. Results. Three prognosis-related PRGs (BAK1, GSDMC, and IL18) were chosen to create a risk model. High-risk patients from the TCGA and ICGC cohorts had an unfavorable overall survival (all p < 0.05 ). The risk modelʼs accuracy and independent predictability were assessed by receiver operating characteristic curves and multivariate Cox regression analysis, respectively. High-risk patients possessed different molecular pathways, higher KRAS and TP53 mutations, increased expression of PD-L1, C1 immune subtype, and immunosuppressive microenvironment characterized by parainflammation compared to low-risk patients. KRAS and TP53 mutations participated in different inflammatory pathways and played different prognostic roles between the two risk groups. KRAS mutations in high-risk patients caused a more unfavorable prognosis than wild-type KRAS ( p = 0.016 ), whereas TP53 mutations in low-risk patients exhibited a poorer outcome than wild-type TP53 ( p = 0.009 ). Spearman correlation analyses revealed that the parainflammatory response in PC might be implicated in GSDMC-mediated pyroptosis via cytosolic DNA-sensing pathways under hypoxic conditions. Furthermore, the risk scores were significantly and positively related to the expression of HNRNPC, RBM15, YTHDF1, and YTHDF2, as well as sensitivity to gemcitabine, cisplatin, and erlotinib. Conclusions. This study created a novel pyroptosis-based risk model related to the parainflammatory immune microenvironment, which might help identify novel biomarkers, evaluate the tumor immune microenvironment, and develop management strategies for PC patients.
... TME is an immunosuppressive environment characterized by the presence of mediators capable of neutralizing immune surveillance, damaging the infiltration of T cells and facilitating the accumulation and activation of regulatory T cells, thus promoting the spread of cancer [2]. Tumor invasion Treg is a major group of immune cells,in various solid tu-mors including gastric [3], lung [4], ovarian [5], pancreatic ductal adenocarcinoma (PDAC) [6], melanomas [7], breast [8] and hepatocellular cancer [4], TI-Treg can account for more than 50% of all CD4+ T cells.Because the infiltration of large amounts of Treg into the tumor in the immunosuppressive tumor microenvironment will hinder the development of effective anti-tumor immunity and is often associated with poor prognosis [9][10][11]. ...
... Tregs suppress the T effector (T-eff) cells through inhibitory cytokines such as transforming growth factor (TGF)-β, interleukin (IL)-10, direct cytotoxicity through perforins/granzyme, promotion of T cell exhaustion and thus prevent the tumor-specific immune response which leads to resistance to ICI [24][25][26] . The proportion of Tregs has predictive and prognostic values [27][28][29] . In a study by Griffiths et al., a high frequency of Tregs in the peripheral blood of RCC patients was found to be associated with reduced survival [30] . ...
The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.
... TILs and decreased CD8 ? TILs in PDAC [36]. We re-analyzed 147 patients, excluding poorly differentiated adenocarcinoma, and obtained similar results. ...
Background:
Abundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC.
Methods:
We performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4+ tumor-infiltrating lymphocytes [TILs], CD8+ TILs, FOXP3+ TILs, and tertiary lymphoid structures), and patient prognosis.
Results:
Low amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41-12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08-4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59-3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36-5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34-6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4+ TILs (P = 0.046), CD8+ TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001).
Conclusions:
Tumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes.
... In this study, the high-risk patients had lower proportions of B cells, CD8+ T cells, and Tregs. Many studies have shown that the proportion of Treg cells is positively related to the poor prognosis of PC patients, which is inconsistent with our results [40]. However, recent studies reported that the depletion of Treg cells led to the acceleration of tumour progression in PC, which might explain the lower proportion of Tregs in the high-risk group [41]. ...
The correlation between dysregulation of splicing and cancers has been increasingly recognised and confirmed. The identification of valuable alternative splicing (AS) in pancreatic head cancer (PHC) has a great significance. AS profiles in PHC were generated using the data from The Cancer Genome Atlas and TCGASpliceSeq. Then, the NMF clustering method was performed to identify overall survival-associated AS (OS-AS) subtypes in PHC patients. Subsequently, we used least absolute shrinkage and selection operator Cox regression analysis to construct an AS-related risk model. The splicing regulatory network was uncovered by Cytoscape 3.7. A total of 1694 OS-AS events were obtained. The PHC patients were divided into clusters 1 and 2. Cluster 1 had poorer prognosis and lower infiltration of immune cells. Subsequently, a prognostic signature was established that showed good performance in predicting OS and progression-free survival. The risk score of this signature was associated with the unique tumour immunity. Moreover, a nomogram incorporating the risk score and clinicopathological parameters was established. Finally, a splicing factor-AS regulatory network was developed. A comprehensive analysis of the AS events in PHC associated with prognosis and tumour immunity may help provide reliable information to guide individual treatment strategies.
... The presence of intratumoral CD8 + T cells as well as the polarization of conventional CD4 + T (Tconv) cells toward a Th1 phenotype were both associated with prolonged survival in human PDAC, whereas Th2 cells promoted tumor progression in murine pancreatic cancer (15,(17)(18)(19). Furthermore, high levels of immunosuppressive Tregs in the peripheral blood and tumor stroma were associated with poor clinical outcomes in human PDAC (20,21). These data were almost entirely derived from limited immunohistochemical analyses, while functional studies are lacking. ...
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.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.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.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.
... CD4 + T cells include Tregs and CD4 + helper 17 (Th17), both of which exert tumor-promoting functions [71] . Tregs express a CD3 + CD4 + CD25 + FoxP3 + phenotype and are associated with poor prognosis [72,73] . Tregs communicate intimately with MDSCs primarily through cell-cell interactions to promote their survival and promote an immunosuppressive TME [74] . ...
Over the past decade, researchers have identified and characterized the diverse cell populations within the tumor microenvironment of pancreatic cancer. The interplay between these cells in the TME either promotes or inhibits the malignant behavior of pancreatic cancer cells. Cancer-associated fibroblasts, previously thought to be one main subset, can now be broadly subclassified into three main types: inflammatory, myofibroblastic, and antigen-presenting, with the former and the latter two exerting pro-tumoral and anti-tumoral functions, respectively. Myeloid cells include myeloid-derived suppressor cells and tumor-associated macrophages. Myeloid-derived suppressor cells can be further divided into polymorphonuclear and monocytic and exhibit pro-tumoral activities. Tumor-associated macrophages exhibit M1 (anti-tumoral) or M2 (pro-tumoral) phenotypes, which are present in a dynamic fashion between the two phenotypes. Other constituents of the immune make-up of the tumor microenvironment include T and B cells and less described subsets which include natural killer cells, γδ T cells, and group 2 innate lymphoid cells. This review provides an overview of the studies that lead to the discovery of those cellular populations and highlights the recent efforts to utilize them as therapeutic targets in pancreatic cancer.
... Chen et al. have developed a prognostic signature for head and neck squamous cell carcinoma via IRGs, which could effectively distinguish the prognosis, the molecular and immune characteristics, and immune benefit from immune checkpoint inhibitor therapy [15]. ese researches determined that immune-related predictive biomarkers could enhance immunotherapy efficacy [16,17]. Screening of prognostic biomarkers via IRGs has without question been immune therapy of cancer research hotspot. ...
Pancreatic adenocarcinoma (PAAD) carries the lowest survival rate of all major organ cancers, which is of dismal prognosis and high mortality rate. Thus, the present study attempted to identify a few novel prognostic biomarkers and establish an immune-related prognostic signature which could predict the prognosis of PAAD. Four prognostic immune-related genes (IRGs) including S100A6, S100A10, S100A16, and SDC1 were screened by differentially expressed gene (DEG) identification and weighted gene coexpression network analysis (WGCNA). Subsequent analysis proved the high expression of these IRGs in PAAD tissues, suggested by TCGA-PAAD data, merged microarray-acquired dataset (MMD), GEPIA, and Oncomine webtool. By using MMD and TCGA-PAAD data, S100A6 (MMD: AUC = 0.897; TCGA: AUC = 0.843), S100A10 (MMD: AUC = 0.880; TCGA: AUC = 0.780), S100A16 (MMD: AUC = 0.878; TCGA: AUC = 0.838), and SDC1 (MMD: AUC = 0.885; TCGA: AUC = 0.812) exhibited excellent diagnostic efficiency for PAAD. By conducting connectivity map (CMap) analysis, we concluded that three molecule drugs (sulpiride, famotidine, and nalidixic acid) might have worked in the treatment of PAAD. Then, an immune-related prognostic index was constructed, which was validated as an independent prognostic factor for PAAD patients ( P = 0.004 ). We further constructed a nomogram by using this immune-related signature and age, the prognostic value of which was validated by using concordance index (C-index = 0.780) and area under curve (AUC = 0.909). Moreover, the immune-related prognostic signature was associated with response to anti-PD-1/L1 immunotherapy. To sum up, four IRGs were screened out and verified to be novel immune-related prognostic biomarkers in PAAD. Besides, sulpiride, famotidine, and nalidixic acid might be potential choices in the treatment of PAAD. An immune-related signature was established to show great potential for prognosis prediction for PAAD, independently, which might guide more effective immunotherapy strategies. A nomogram is further established by using this immune-related prognostic index, which might contribute to more effective prognosis prediction in PAAD patients.
... These results are in line with the results of research conducted by Almangush et al. [26] with patients in non-endemic countries with NPC and Wang et al. [29] with patients in NPC endemic countries. An increase in the ratio of Foxp3 to CD4 and CD8 was also obtained in the study of Tang et al. [30] in patients with pancreatic ductal adenocarcinoma who explained that tumor tissue infiltrated by lymphocytes showed increased Foxp3, CD4, and CD8 expression compared to normal pancreatic tissue as a control group. As the role of lymphocytes as cells that mediate inflammation to eliminate tumor cells and followed by an increase in the expression of CD4, CD8, and Foxp3 Treg cells in the tumor environment, the increased expression of CD4, CD8, and Foxp3 can be directly proportional to the increase in lymphocyte infiltration in the tumor area. ...
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a carcinoma originating from the surface epithelium of the nasopharynx with the highest incidence in China and South East Asia. Currently, many researchers are developing tumor microenvironment which can be assessed by tumor-infiltrating lymphochyte, and its association with treatment response in several tumors, including NPC. Foxp3, known as a regulatory T cell (Treg) marker, plays a role in the immunoregulatory environment of tumor cells and can be used as a prognostic factor. The relationship between Foxp3 expression and treatment response is considered as one of the factors affecting the prognosis of NPC. AIM: This study aims to determine the relationship between Foxp3 expression and treatment response in NPC. MATERIALS AND METHODS: A cross-sectional study was done to analyze the association between Foxp3 and treatment response in NPC. This study included 60 samples who were diagnosed with non-keratinizing NPC at the Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Cipto Mangunkusumo Hospital from January 2018 until December 2020. Immunohistochemistry was done to evaluate the expression of Foxp3. Foxp3 expression was evaluated in the intratumoral and peritumoral areas. RESULTS: Among 60 patients, the number of males were more than females (66.7%, 33.3%, respectively) with a ratio of 2:1. There was statistically significant difference between intratumoral and total Foxp3 expression and treatment response (p < 0.05, p = 0.001, respectively); however, no significant differences found between peritumoral Foxp3 expression and treatment response (p = 0.114). CONCLUSION: Foxp3 expression had a statistically significant relationship with response therapy after chemoradiation.
... Therefore, the level of CD8+ T lymphocyte in ltration in PDAC is lower than that in paracarcinoma tissue. This might be related to the tumour immune escape mechanism (4). There are a variety of abnormally expressed chemokines and their receptor axes in the tumour microenvironment, which play a signi cant role in tumour migration, invasion, angiogenesis, late metastasis and the growth of various intercellular cells (5). ...
Background: Pancreatic cancer is a malignant disease with difficult diagnosis and high mortality. The most common type is pancreatic duct adenocarcinoma (PDAC). CXCL10 is of great significance in the treatment of immune diseases and cancer. Here, we evaluated the expression of CXCL10 in pancreatic cancer and its clinical significance.
Results: The results of the TCGA database showed that the expression of CXCL10 in pancreatic cancer tissues was higher than that in matched adjacent tissues (P <0.05). Patients with high expression of CXCL10 had a poor prognosis compared with those with low expression of CXCL10 (P=0.0051).We found that CXCL10 was positively and strongly correlated with tumour-infiltrating neutrophils and macrophages in PDAC (P<0.0001). We also performed CXCL10 immunohistochemical staining in a tissue microarray (TMA), which included tumour samples collected from 119 PDAC patients (each sample was matched with an adjacent tissue sample). The expression level of CXCL10 in PDAC tissues was prominently higher than that in the matched adjacent tissues (P = 0.0001). Analysis of clinicopathological factors suggested that the high expression of CXCL10 was correlated with the patient's T stage (P = 0.020). In addition, higher CXCL10 expression was significantly associated with worse overall survival of PDAC patients (P = 0.012). The results of COS multivariate analysis suggested that age (P=0.005), histological grade (P=0.001), TNM stage (P=0.017) and CXCL10 expression (P=0.024) were independent prognostic factors for pancreatic cancer.
Conclusion: Our data indicate that CXCL10 is highly expressed in PDAC and may be used as an independent clinical prognostic indicator for PDAC.
