Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka, Didem; Gökalp, Muazzez; Piyade, Betul; Cevik, Nedim Can; Sever, Elif Arik; Unutmaz, Derya; Ceyhan, Güralp O.; Demir, Ihsan Ekin; Asimgil, Hande

doi:10.3390/cancers12082274

Cited by 89 publications

(79 citation statements)

References 208 publications

(284 reference statements)

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“…IFN-γ is a major mediator inducing the death of tumor cells. However, continuous exposure to IFN-γ also stimulates tumor cells to express multiple inhibitory modulators including PD-L1 which are majorly enriched in C2 and C3 in our study, thereby suppress the secretion of IFN-γ by effector T cells and result in T cell exhaustion [24,25]. Together, a more prominent feature of immunosuppression may be promoted by these features of C2 and therefore the prognosis of C2 is worse.…”

Section: Discussionmentioning

confidence: 60%

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Liu

Zhang

et al. 2021

Cancer Cell Int

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Background Emerging evidence has shown that intra-tumor immune features are associated with response to immune checkpoint blockade (ICB) therapy. Accordingly, patient stratification is needed for identifying target patients and designing strategies to improve the efficacy of ICB therapy. We aimed to depict the specific immune features of patients with pancreatic cancer and explore the implication of immune diversity in prognostic prediction and individualized immunotherapy. Methods From transcriptional profiles of 383 tumor samples in TCGA, ICGC, and GEO database, robust immune subtypes which had different response immunotherapy, including ICB therapy, were identified by consensus clustering with five gene modules. DEGs analysis and tumor microarray were used to screen and demonstrate potential targets for improving ICB therapy. Results Three subtypes of pancreatic cancer, namely cluster 1–3 (C1–C3), characterized with distinct immune features and prognosis, were generated. Of that, subtype C1 was an immune-cold type in lack of immune regulators, subtype C2, with an immunosuppression-dominated phenotype characterized by robust TGFβ signaling and stromal reaction, showed the worst prognosis, subtype C3 was an immune-hot type, with massive immune cell infiltration and in abundance of immune regulators. The disparity of immune features uncovered the discrepant applicability of anti-PD-1/PD-L1 therapy and potential sensitivity to other alternative immunotherapy for each subtype. Patients in C3 were more suitable for anti-PD-1/PD-L1 therapy, while patients in the other two clusters may need combined strategies targeted on other immune checkpoints or oncogenic pathways. A promising target for improving anti-PD-1/PD-L1 treatment, TGM2, was screened out and its role in the regulation of PD-L1 was investigated for the first time. Conclusion Collectively, immune features of pancreatic cancer contribute to distinct immunosuppressive mechanisms that are responsible for individualized immunotherapy. Despite pancreatic cancer being considered as a poor immunogenic cancer type, the derived immune subtypes may have implications in tailored designing of immunotherapy for the patients. TGM2 has potential synergistic roles with ICB therapy.

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Section: Discussionmentioning

confidence: 60%

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Liu

Zhang

et al. 2021

Cancer Cell Int

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“…Lymphocytes are important cellular components of the human immune response system that help to fight tumours by inhibiting cancer cell proliferation, invasion and migration [ 30 ]. Saka et al [ 31 ] reported that T cell exhaustion was closely associated with poor prognosis in cancer. Cholesterol plays a vital role in modulating the activity of membrane proteins, which may be associated with the occurrence and development of cancer and interactions with the body’s immune system.…”

Section: Discussionmentioning

confidence: 99%

Preoperative Controlling Nutritional Status (CONUT) score predicts short-term outcomes of patients with gastric cancer after laparoscopy-assisted radical gastrectomy

et al. 2021

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Background An emerging prediction tool, the Controlling Nutritional Status (CONUT) score, has shown good assessment ability of postoperative outcomes in cancer patients. This study evaluated the role of the preoperative CONUT score regarding the short-term outcomes of gastric cancer (GC) after laparoscopic gastrectomy. Methods Three hundred and nine GC patients undergoing laparoscopic gastrectomy from January 2016 to June 2019 were analysed, retrospectively. The patients were divided into two groups according to the CONUT optimal cut-off value. Clinical characteristics and postoperative complications in the two groups were analysed and evaluated. Risk factors for complications were identified by univariate and multivariate analyses. Results A total of 309 patients underwent laparoscopic gastrectomy; 91 (29.4%) patients experienced postoperative complications. The preoperative CONUT score showed a good predictive ability for postoperative complications (area under the curve (AUC) = 0.718, Youden index = 0.343) compared with other indices, with an optimal cut-off value of 2.5. Patients with high CONUT score had a significantly higher incidence of overall complications (P < 0.001). Age, haemoglobin, C-reactive protein, red blood cell levels, CONUT scores, surgical procedure type, T1, T4, N0 and N3 pathological TNM classification, and pathological stages of I and III were associated with postoperative complications (P < 0.05). Furthermore, the preoperative CONUT score was identified as an independent risk predictor of postoperative complications (P = 0.012; OR = 2.433; 95% CI, 1.218-4.862) after multivariate analysis. Conclusions The preoperative CONUT score is a practical nutritional assessment for predicting short-term outcomes in GC patients after laparoscopy-assisted gastrectomy.

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“…It is worth reminding that our results did not contradict previous findings that high infiltration of CD8 + T cells indicated beneficial prognosis, but extended and enriched this conclusion. In the recent literature, tumor with higher CD8 + T cell infiltration, but T cell dysfunction and increased immune escape result in a poor prognosis ( Hossain et al, 2020 ; Saka et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

Liu

et al. 2021

Front. Genet.

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A growing amount of evidence has suggested the clinical importance of stromal and immune cells in the liver cancer microenvironment. However, reliable prognostic signatures based on assessments of stromal and immune components have not been well-established. This study aimed to identify stromal-immune score–based potential prognostic biomarkers for hepatocellular carcinoma. Stromal and immune scores were estimated from transcriptomic profiles of a liver cancer cohort from The Cancer Genome Atlas using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumors using Expression data) algorithm. Least absolute shrinkage and selection operator (LASSO) algorithm was applied to select prognostic genes. Favorable overall survivals and progression-free interval were found in patients with high stromal score and immune score, and 828 differentially expressed genes were identified. Functional enrichment analysis and protein–protein interaction networks further showed that these genes mainly participated in immune response, extracellular matrix, and cell adhesion. MMP9 (matrix metallopeptidase 9) was identified as a prognostic tumor microenvironment–associated gene by using LASSO and TIMER (Tumor IMmune Estimation Resource) algorithms and was found to be positively correlated with immunosuppressive molecules and drug response.

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Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Cited by 89 publications

References 208 publications

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Preoperative Controlling Nutritional Status (CONUT) score predicts short-term outcomes of patients with gastric cancer after laparoscopy-assisted radical gastrectomy

Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

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