Clinicopathological and Prognostic Significance of Immunoscore and PD-L1 in Intrahepatic Cholangiocarcinoma

Wu, Hong; Wei, Yulong; Mei, Jian; Li, Hong; Song, Qibin; Hao, Liheng; Yue, Yong

doi:10.2147/ott.s288982

Cited by 13 publications

(17 citation statements)

References 33 publications

(43 reference statements)

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“…Ying Zhu and colleagues found that INF-g secretion by CD8+ T cells may increase cancer cell PD-L1 expression (34). Upregulated PD-L1 on cancer cells has been recognized as a marker of immune escape and poor outcome in patients with cholangiocarcinoma (35). Consistent with this, we found higher levels of PD-L1 expression in the high-risk group.…”

Section: Discussionsupporting

confidence: 88%

Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

et al. 2021

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BackgroundCholangiocarcinoma is an aggressive carcinoma with increasing incidence and poor outcomes worldwide. Genomic instability and alternative splicing (AS) events are hallmarks of carcinoma development and progression. The relationship between genomic instability, AS events, and tumor immune microenvironment remain unclear.MethodsThe splicing profiles of patients with cholangiocarcinoma were obtained from The Cancer Genome Atlas (TCGA) spliceSeq database. The transcriptomics, simple nucleotide variation (SNP) and clinical data of patients with cholangiocarcinoma were obtained from TCGA database. Patients were divided into genomic unstable (GU-like) and genomic stable (GS-like) groups according to their somatic mutations. Survival-related differential AS events were identified through integrated analysis of splicing profiling and clinical data. Kyoto Encyclopedia of Genes and Genomes enrichment analysis was used to identify AS events occurring in genes enriched in cancer pathways. Pearson correlation was applied to analyze the splicing factors regulating AS events. CIBERSORT was used identify differentially infiltrating immune cells.ResultsA prognostic signature was constructed with six AS events. Using this signature, the hazard ratio of risk score for overall survival is 2.362. For TCGA patients with cholangiocarcinoma, the area under the receiver operating characteristic curve is 0.981. CDK11A is a negative regulator of survival associated AS events. Additionally, the CD8+ T cell proportion and PD-L1 expression are upregulated in patients with cholangiocarcinoma and high splicing signatures.ConclusionWe provide a prognostic signature for cholangiocarcinoma overall survival. The CDK11A splicing factor and SLC46A1-39899-ES and IARS-86836-ES AS events may be potential targets for cholangiocarcinoma therapy. Patients with high AS risk score may be more sensitive to anti-PD-L1/PD1 immunotherapy.

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Section: Discussionsupporting

confidence: 88%

Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

et al. 2021

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“…In 11 of the 33 studies, the distribution of TILs between peritumoral and intratumoral areas in CCA was studied [ 17 , 18 , 20 , 23 , 26 , 27 , 29 – 33 ] (Table 2 ). For iCCA, 5 studies show that CD8+, CD4+ and CD3+ T cells mainly distributed around the cancer itself [ 17 , 18 , 26 , 29 , 30 ]. One study observed Foxp3+ T cells directly infiltrating into the tumor [ 18 ], while another study could not support these results [ 17 ].…”

Section: Resultsmentioning

confidence: 99%

“… [ 30 ] Xu YP 2021 China iCCA (140) IT CD8+ IHC Median (cell count, x400 HPF) 25 (median) OS / DFS High count of infiltrating CD8+ cells is related to longer OS and DFS. [ 26 ] Tian L 2020 China iCCA (322) IT CD8+ mIHC Median (cell count, x400 HPF) 27 (median) OS / TTR Patients with a high density of CD8+ T cells displayed longer OS ( p =0.006) and more favorable TTR ( p =0.003) [ 29 ] Wu H 2021 China iCCA (50) IT / TM CD8+ IHC Median (cell count, x200 HPF) 26.5 (median) OS / RPF A higher number of CD8+ cells in the tumor margin is associated with prolonged OS and RFS ( p =0.048, p =0.033). [ 20 ] Kim H 2021 Korea CCA (52) IT / TM FoxP3-CD4+ mIHC Median (cell count, x400 HPF) Not reported OS / RFS A high density of FoxP3-CD4+ cells in the tumor margin is independently associated with favorable DFS and OS ( p =0.005, p =0.004).…”

Section: Resultsmentioning

confidence: 99%

“…In the analysed literature within this systematic review, different immune cells and their subtypes had different prognostic implications for the long-term outcome in CCA. CD8+T cells show a significant association with prolonged OS irrespective of being detected inside [ 17 , 29 ] or outside [ 18 ] of the tumor. A high density of CD4+ T cells in the tumor margin appeared also to be independently associated with favorable DFS and OS [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

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The role of tumor-infiltrating lymphocytes in cholangiocarcinoma

Heij

Czigány

Dahl

et al. 2022

J Exp Clin Cancer Res

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Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients.In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA.In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translationaldata is needed to fully unravel the importance of TILs in the treatment of CCA.

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“…A consensus about immune score construction has not yet been reached in gastric cancer. In some studies, a cutoff value, usually the median [ 22 , 36 ], is given for each marker to distinguish low infiltrating levels (score 0) from high infiltrating levels (score 1). By combining 2 markers in 2 regions together, patients obtain scores of 0 to 4.…”

Section: Discussionmentioning

confidence: 99%

Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy

Zou

Zhou

Zhang

et al. 2021

Journal of Oncology

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Background. Substantial evidence has demonstrated that tumor-infiltrating lymphocytes (TILs) are correlated with patient prognosis. The TIL-based immune score (IS) affects prognosis in various cancers, but its prognostic impact in gastric cancer (GC) patients treated with adjuvant chemoradiotherapy remains unclear. Methods. A total of 101 GC patients who received chemoradiotherapy after gastrectomy were retrospectively analyzed in this study. Immunohistochemistry staining for CD3+ and CD8+ T-cell counts in both tumor center (CT) and invasive margin (IM) regions was built into the IS. Patients were then divided into three groups based on their differential IS levels. The correlation between IS and clinical parameters was analyzed. The prognostic impact of IS and clinical parameters was evaluated using Kaplan–Meier analysis and Cox proportional hazard regression analysis. Receiver operating characteristic (ROC) curves were plotted to compare the area under the curve (AUC) of IS with other clinical parameters. Nomograms for disease-free survival (DFS) and overall survival (OS) prediction were constructed based on the identified parameters. Results. Finally, 20 (19.8%), 57 (56.4%), and 24 (23.8%) GC patients were identified with low, intermediate, and high IS levels, respectively. GC patients with higher IS levels exhibited better DFS ( p < 0.001) and OS ( p < 0.001). IS was an independent prognostic factor for both DFS ( p < 0.001) and OS ( p < 0.001) in multivariate analysis. IS presented a better predictive ability than the traditional pathological tumor-node-metastasis (pTNM) staging system (AUC: 0.801 vs. 0.677 and 0.800 vs. 0.660, respectively) with respect to both DFS and OS. The C-index of the nomograms for DFS and OS prediction was 0.737 and 0.774, respectively. Conclusions. IS is a strong predictive factor for both DFS and OS in GC patients treated with adjuvant chemoradiotherapy, which may complement the traditional pTNM staging system.

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Clinicopathological and Prognostic Significance of Immunoscore and PD-L1 in Intrahepatic Cholangiocarcinoma

Cited by 13 publications

References 33 publications

Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

The role of tumor-infiltrating lymphocytes in cholangiocarcinoma

Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy

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