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Objective: To investigate the correlation between programmed death ligand-1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) and evaluate the prognostic value of PD-L1 and TILs in Chinese triple-negative breast cancer (TNBC) patients with different molecular subtype METHODS: This retrospective study was conducted at 2020. Specifically, the pre-chemotherapy clinical data and non-stained tissue blocks of 465 TNBC patients visited the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014 were collected, with their blocks sliced and stained using PD-L1(SP142), and the outcome of subsequent chemotherapy obtained in 2020. The relapse-free survival (RFS) of the study population was calculated. The baseline PD-L1 expression status correlations with TILs and molecular subtypes were assessed using Spearman's rank correlation analysis and the Kruskal-Wallis test. Kaplan-Meier survival analyses were undertaken to evaluate the prognosis value of TILs and PD-L1 expression., Results: PD-L1 expression status on IC was moderately and positively correlated with stromal tumor-infiltrating lymphocytes (sTILs) (r s = 0.502, P <0.001) and iTILs (r s = 0.410, P < 0.001), respectively. PD-L1 expression status and TILs showed significant differences among molecular subtypes (P < 0.001), with the highest proportion of PD-L1+ and high TILs patients observed in the immunomodulatory (IM) subtype. TILs were significantly associated with RFS. Moreover, sTILs could act as an independent predictor of RFS (RR 0.953, 95 % CI 0.920 ∼ 0.987, P = 0.007), while PD-L1 expression status did not show the same prognostic significance., Conclusions: The incorporation of pre-treatment TILs and PD-L1 expression status as valuable tools for optimizing patient selection for immunotherapy and managing the risks associated with chemotherapy in Chinese TNBC patients., Data Availability: The data sets generated and analyzed during the current study are available from the corresponding author., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

BACKGROUND Tumor-infiltrating immune cells (TIICs) are implicated in the survival of ovarian cancer (OVCA) patients, but their prognostic significance in advanced or metastatic OVCA patients treated with neoadjuvant chemotherapy (NCAT) has not been well documented, particularly in the Chinese population. MATERIAL AND METHODS A total of 31 advanced or metastatic OVCA patients who underwent NACT were included. The density and positive rate of tumor-infiltrating immune cells (TIICs) within cancer cell nests and in cancer stroma were explored. The correlations of pre- or post-NACT TIICs with the efficacy of NACT and the changes in TIIC subpopulation with NACT were examined. RESULTS Compared with patients with partial benefit from NACT, significantly decreased pre-NACT intratumoral CD68⁺CD163⁺ cells (P=0.0043) and increased pre-NACT intratumoral CD56⁺ cells (P=0.038) were observed in patients with benefit. The high level of pre-NACT intratumoral CD68⁺CD163⁻ M1 macrophage (P=0.075) and stromal CD3⁺PD-1⁺ cells (P=0.085) predicated improved progression-free survival, respectively. Increased post-NACT stromal CD68⁺CD163⁻ M1 macrophage (P=0.01), stromal CD8⁺ T cells (P=0.073), and stromal CD8⁺PD-1⁺ cells (P=0.072) were associated with benefit from NACT. Moreover, NACT increased intratumoral CD3⁺ (P=0.031), CD8+ (P=0.031), and CD3⁺CD8⁺ cells (P=0.031). CONCLUSIONS High intratumoral CD68⁺CD163⁻, intratumoral CD56⁺ cells, and stromal CD3⁺PD-1⁺ cells pre-NACT predicted good prognosis. Intratumoral CD3⁺, CD8⁺, and CD3⁺CD8⁺ cells were increased after NACT. Evaluation of immune profiles may help to identify patients who might benefit from NACT and allow us to further stratify advanced or metastatic OVCA patients treated with NACT for disease management.

Background: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8 + T cell in SCCE for the first time., Materials and Methods: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density., Results: No patients had PD-L1 expressed in their tumor cells. PD-L1 + expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68 + monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression ( Ptrend <0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS., Conclusion: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Diffuse lower-grade gliomas (LGG) represent the highly heterogeneous and infiltrative neoplasms in the central nervous system (CNS). Replication factor C 2 (RFC2) is a subunit of the RFC complex that modulates DNA replication and repair. However, the prognosis value of RFC2 and its association with the immune signature of tumor microenvironment (TME) in LGG remains unknown. Based on Oncomine, TCGA, GTEx, TIMER, GEPIA, and HPA databases, we evaluated RFC2 expression levels and its clinical prognostic value in LGG and other cancers. Then we analyzed the correlations between RFC2 expression and tumor mutation burden (TMB), tumor microsatellite instability (MSI), and mismatch repair (MMR) genes across cancers. And CIBERSORT and ESTIMATE algorithms were conducted to estimate the association of RFC2 with immune cell infiltration of LGG. Additionally, we performed the functional enrichment analyses of RFC2 in LGG. Then functional experiments were employed to further validate the oncogenic role of RFC2 in LGG. Our results showed that RFC2 was widely highly expressed in most types of cancer. And its expression was closely related to the clinicopathological features and prognosis in LGG and other cancer types. RFC2 levels were also correlated with TMB and MSI across various cancers. Furthermore, RFC2 was positively associated with the infiltration levels of immune cells and immune checkpoint genes in LGG. Additionally, in vitro experiments revealed that RFC2 played an oncogenic role in LGG progression. In conclusion, our findings revealed that RFC2 could serve as a reliable biomarker to predict the prognosis and immune signature for LGG., (© 2022. The Author(s).)

CD74 was initially thought to participate mainly in antigen presentation as an MHC class II chaperone. Recent studies have shown that CD74 plays an important role within the cell and throughout the immune system in a wide spectrum of neoplasms. However, the role of CD74 in hepatocellular carcinoma (HCC) remains elusive. In this study, HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas (TCGA) were obtained and analyzed. Immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq) were performed to detect the characteristics of CD74 + cells and explore their impact on the tumor microenvironment (TME) of HCC. Our data revealed that stromal CD74 + cell enrichment was associated with favorable prognosis in patients with HCC. CD74 was abundant in a large portion of HCC specimens and prominently distributed on stromal macrophages. scRNA-seq data also indicated that the pathways related to immune response were significantly upregulated in CD74 + macrophages. High infiltration of CD74 + macrophages was associated with increased infiltration of CD8 + cytotoxic T lymphocytes (CTLs) with enhanced effector functions in HCC. Besides, blocking CD74 weakened the antitumor activity and proliferation ability of CD8 + CTLs in HCC. Our findings highlight the critical role of CD74 in HCC. New drugs and antibodies targeting CD74 may be effective strategies for HCC therapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Novel systemic agents and effective treatment strategies for recurrence adenoid cystic carcinoma (ACC) of the head and neck are still worthy of further exploration. Here, we analyzed the mutations and expression profiles of 75 Chinese ACC patients, characterized the prognostic value of the immune signature for recurrence or distant metastasis, and explored the potential of immunotherapeutic biomarkers in ACC. In general, MYB fusion and somatic mutations accounted for a high proportion, which was 46.7% (35/75). ACCs displayed an overall low mutation burden and lack of programmed cell death ligand-1 (PD-L1) expression. The antigen-presenting machinery (APM) expression score and immune infiltration score (IIS) were the lowest among ACC patients, compared with other cancer types. For 61 primary cases, the locoregional recurrence-free survival (LRRFS) was statistically significantly correlated with the IIS [univariate analysis; hazard ratio (HR) = 0.32; 95% CI, 0.11-0.92; p = 0.035] and T-cell infiltration score (TIS) (univariate analysis; HR = 0.33; 95% CI, 0.12-0.94; p = 0.037]. Patients with lower IIS (log-rank p = 0.0079) or TIS (log-rank p = 0.0079) had shorter LRRFS. Additionally, solid pattern was also a prognostic factor related to locoregional recurrence, whereas postoperative radiotherapy (PORT) exerted its beneficial effects. We further evaluated the pretreatment immune profile of five ACC patients treated with PD-1 inhibitors. Patients who responded to camrelizumab or pembrolizumab observed elevated APM and TIS, compared with patients with progressive disease. Our study highlights the immune infiltration pattern and messenger RNA (mRNA) signatures of Chinese ACC patients, which has the potential value for prognosis and immunotherapy., Competing Interests: DC, NH, MZ, YNY, GDZ, and YDY were employed by the company GloriousMed Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dou, Li, He, Zhang, Jiang, Ye, Yang, Zhao, Yang, Li, Chen and Zhu.)

Background: Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response against cancer and tertiary lymphoid structures (TLS) may contribute to lymphocytes recruitment. Both of them have been reported as potential prognostic parameters in some human malignancies. However, the roles of TILs, TLS, and their correlation in Epstein-Barr Virus-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC) are largely unknown., Methods: To observe the correlation among TILs, TLS, and clinicopathological characteristics and their prognostic significance in EBVaGC and EBVnGC, respectively. TILs and TLS were assessed by morphology and/or immunohistochemistry, and accompanied by clinicopathological analysis from 846 gastric cancer patients in multiple institutions., Results: Forty-two (5.0%) cases of EBVaGC and 804 cases of EBVnGC were identified by in situ hybridization, respectively. For EBVnGC, higher TILs grade was correlated with TLS-present. EBVnGC patients with high TILs grade and TLS-present exhibited survival benefits. TILs ( P = 0.001) and TLS ( P = 0.003), especially TILs & TLS ( P < 0.001) were independent prognostic factors in EBVnGC. A nomogram was constructed and validated for predicting the probability of overall survival and performed well with a good calibration. No significant prognostic value was detected in EBVaGC., Conclusion: TILs and TLS, especially TILs & TLS were promising prognostic indicators for overall survival in EBVnGC. TILs and TLS were highly overlapping in their extent and prognostic abilities, and may be considered as a coindicator of prognosis of gastric cancer. The evaluations of TILs and TLS are simple and can be assessed routinely in pathological diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cheng, Li, Cheng, Zhao, Dong, Zhang, Zhao, Chen and Shao.)

Background & Aims: Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China., Methods: We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing., Results: EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC., Conclusions: EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy., Lay Summary: Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aims: To assess the expression and epigenetic regulation of Syncoilin, intermediate filament protein ( SYNC ) in gastric cancer tissues, and to determine its associations with clinicopathological features; immune infiltration of macrophages in tumors; and patient survival. Materials and Methods: Clinicopathological features, expression profiles, and methylation data of the SYNC gene were obtained from multi-institutional real-world public datasets. A total of 1601 samples from patients with gastric cancer were examined. The associations between clinicopathological features and SYNC expression levels were assessed by the chi-square test; survival was assessed using the Kaplan-Meier analysis. The infiltration levels of M1, 2-polarized tumor-associated macrophages (TAMs) in a gastric tumor immune microenvironment were quantified using deconvolution, and the correlation between SYNC expression level and M1, 2-polarized macrophages' infiltration was examined using the Pearson correlation test. SYNC gene methylation data were analyzed to investigate epigenetic control of its expression. Results: SYNC expression was elevated in gastric cancer tissues ( p  < 0.01), and was associated with a poorer overall survival ( p  < 0.01) and poorer postprogression survival ( p  = 0.01). Higher SYNC levels were significantly associated with more aggressive clinicopathological features in gastric cancer patients ( p  < 0.05). SYNC was also associated with the infiltration of M2-polarized TAMs in the gastric tumor immune microenvironment ( p  < 0.001). Hypomethylation was shown to be associated with SYNC' s upregulation ( p  < 0.05). Conclusion: SYNC is highly expressed in gastric cancer tissues and has the potential to be a therapeutic target and to serve as a prognostic marker.

Objective: Currently, there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors (ICIs) for patients with gastric cancer (GC). Homologous recombination deficiency (HRD) can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response. We aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic response., Methods: A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with GC. Correlations between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets (TCGA and MSK-IMPACT)., Results: Fifty-one of the 484 (10.54%) patients carried at least one somatic mutation in an HR gene; ATM (16/484, 3.31%) was among the most frequently mutated HR genes in the Chinese cohort. Mutations in HR genes were associated with elevated tumor mutational burden, enhanced immune activity, and microsatellite instability status. In the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs, patients with HR-mut GC ( n = 12) had significantly better overall survival than those with HR-wt GC ( n = 37) (log-rank test, P < 0.05)., Conclusions: Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy., Competing Interests: Conflict of interest statement No potential conflicts of interest are disclosed., (Copyright: © 2020, Cancer Biology & Medicine.)

Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8 + T-cell-mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p-AKT/p-ERK/p-MEK in tumor tissue. The frequency of tumor CD8 + T cells was significantly elevated in propranolol-treated mice. The expression of GzmB/IFN-γ/T-bet in the CD8 + T-cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol-treated surgical specimens, the expression of p-ERK was decreased and the frequency of CD8 + was significantly elevated. The expression of GzmB in the CD8 + T-cell population was significantly increased in propranolol-treated subjects. Together, these data show propranolol simultaneously activating autologous CD8 + T cells and decreasing the expression of p-AKT/p-ERK/p-MEK in mouse tumor models, while inhibiting the expression of p-ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Recent studies demonstrate that immune checkpoint inhibitor (ICI) therapy has achieved success in many types of advanced cancers including advanced hepatocellular carcinoma (HCC). However, ICI therapy is beneficial in only some HCC patients, suggesting that immune-responses are highly variable in HCCs. Therefore, understanding the immune status in HCC microenvironment will facilitate ICI immunotherapy and guide patient selection for the therapy. In this study, we first analyzed the expression profile of immune-modulating genes and their relationship with survival of HCC patients using the data downloaded from The Cancer Genome Atlas - Liver Hepatocellular Carcinoma (TCGA-LIHC) database, and found that the higher expressions of CD276 (B7-H3) and CD47 were significantly associated with poor survival. Then we identified 4 immune subtypes of HCCs with different survivals by using the combination expression of B7-H3 (or CD47) and CD8. Patients with B7-H3 low /CD8 high or CD47 low /CD8 high have the best survival while ones with B7-H3 high /CD8 low or CD47 high /CD8 low have the worst survival. The 4 immune subtypes were validated in another 72 HCC patients obtained from South China. In conclusion, our findings suggest that HCC patient prognosis is associated with immunophenotypes by T cell infiltration (CD8 expression) and the expression of the adaptive immune resistance gene (B7-H3 or CD47), and this immune classification system will facilitate HCC patient selection for ICI immunotherapy.

Objective: To investigate the expression and cellular source of IL-17A in human ovarian cancer (OC), benign ovarian tumor (BOT) and borderline ovarian tumor (OBT)., Methods: RT-PCR and immunohistochemistry were used to measure the expression level of IL-17A in human OC tissues. Find concrete source of the elevated IL-17A levels in OC tissues by flow cytometry., Results: We found that IL-17A is expressed at higher levels in OC tissues than in BOT or OBT tissues at both the mRNA and protein levels. Moreover, high tumor IL-17A expression was significantly associated with poor tumor differentiation and positive lymph node status. Flow cytometric analysis demonstrated that significantly higher proportions of tumor-infiltrating IL-17A-producing CD4 + T cells (Th17), CD8 + T cells (Tc17), and γδT cells (IL-17 + γδT) were present in OC tissue compared with BOT tissue. Of these, tumor-infiltrating γδT cells were the predominant source of IL-17A in OC and BOT patients. Finally, we found that the abundance of tumor-infiltrating IL-17 + γδT cells, but not Th17 or Tc17 cells, was positively correlated with larger tumor size and lymph node metastasis in patients with advanced OC. These data suggest that increased tumor-infiltrating IL-17 + γδ T cells may be associated with cancer progression in OC patients., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Immune infiltration of nasopharyngeal carcinoma (NPC) is closely associated with the patients' prognosis. However, previous studies have not interpreted the difference of infiltrating immune cells in NPC.We comprehensively analyzed the tumor-infiltrating immune cells present in NPC for the first time, which was based on a scientific deconvolution algorithm (CIBERSORT) and the gene expression data of GSE64634. The fractions of 22 immune cells were assessed to reveal the associations between normal samples and NPC samples.Profiles of immune infiltration vary significantly between normal samples and NPC samples, and the variation could characterize the individual differences. NPC samples contained a higher proportion for M1 macrophages, whereas memory B cells and CD4 memory resting T cells were relatively lower.Our data suggest that the differences in the infiltrating immune cells in NPC and these differences would probably facilitate patient consultation and individualized treatment.

Objective: Breast cancer has become the most common cancer in women in China, and the clinicopathological features differ from those in Western patients. This study was performed to investigate the distribution of programmed cell death protein 1 (PD-1) + /PD-1 - tumor-infiltrating lymphocytes (TILs) and its association with clinicopathological features among Chinese patients with breast cancer., Methods: In total, 133 consecutive patients with primary breast cancer were recruited into this cross-sectional study from 2012 to 2013. TILs were measured by cell counts under high-power fields (HPFs). Immunohistochemistry was used to detect PD-1 expression on tumor-infiltrating lymphocytes in the microenvironment., Results: The median cell counts of the overall TILs, PD-1 + TILs, and PD-1 - TILs were 80, 18, and 55/HPF, respectively. The number of PD-1 - TILs was significantly lower in older than younger patients (50 vs. 60/HPF). Patients with positive E-cadherin expression had more PD-1 - TILs than patients with negative E-cadherin expression (57 vs. 27/HPF). The Ki-67 index was positively correlated with the cell counts of PD-1 + TILs, and the correlation coefficient was 0.29., Conclusions: PD-1 expression on TILs had different clinicopathological features in Chinese patients with breast cancer. E-Cadherin expression was associated with PD-1 - TILs; however, Ki-67 expression was associated with PD-1 + TILs.

Background & Aims: Adjuvant cytokine-induced killer (CIK) cells treatment has shown potential in reducing the recurrence rate and prolonging the survival of patients with hepatocellular carcinoma (HCC). We aimed to identify the best predictive biomarker for adjuvant CIK cells treatment in patients with HCC after curative resection., Methods: This study retrospectively included 145 pairs of HCC patients by one-to-one propensity score matching. One group received CIK cells transfusion after surgery (surgery-CIK group); the other one group underwent surgery only (surgery-only group). Immunohistochemistry (IHC) was used to measure PD-1, PD-L1, CD4, CD8 and Foxp3 expression in tumour tissues of surgery-CIK group; IHC of PD-1 and PD-L1 was conducted in the surgery-only group., Results: The surgery-CIK group had a significantly higher disease-free survival (DFS) and overall survival (OS) rates compared to the surgery-only group. Of all the intratumoural biomarkers, in the surgery-CIK group, multivariate analysis showed that a high number of PD-1 + tumour infiltrative lymphocytes (TILs) was the only factor that independently predicted favourable OS and DFS. By contrast, in the surgery-only group, no significant correlations between PD-1/PD-L1 expression and survival of patients were identified. Further correlation analysis showed a high number of PD-1 + TILs associated with a high number of both CD4 + and CD8 + TILs in surgery-CIK group., Conclusions: A high number of PD-1 + TILs can serve as a potent biomarker for adopting CIK cells therapy in HCC patients after curative resection., (© 2018 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Purpose: CD8(+) TILs at different tumor sites have diverse clinical attributes, which might result from distinct tumor microenvironments that promote differentiation into distinct subsets. However, only a few markers have been identified that can define CD8(+) T-cell subsets. CD103 is a marker of tissue resident memory CD8(+) T cells. In this retrospective study we investigated the cellular source and clinical significance of CD103 expression in urothelial cell carcinoma of bladder tissues in situ., Materials and Methods: Immunohistochemistry and immunofluorescence were used to identify the cellular source of CD103 in bladder urothelial cell carcinoma tissues. Kaplan-Meier analysis and Cox proportional hazards regression models were applied to estimate overall and recurrence-free survival in 302 patients with bladder urothelial cell carcinoma., Results: CD8(+) T cells but not natural killer cells accounted for most CD103 expressing cells in bladder urothelial cell carcinoma tissues. Notably CD103(+) cells were predominantly located in intratumor regions rather than in associated stroma (p < 0.0001). The density of intratumor CD103(+) TILs was inversely associated with tumor size (p < 0.0001) and could represent a favorable prognostic predictor of overall and recurrence-free survival (p = 0.002 and 0.011, respectively). Moreover, intratumor CD103(+) TILs were positively associated with the expression of cognate ligand E-cadherin in intratumor regions of bladder urothelial cell carcinoma tissues (p = 0.008)., Conclusions: Our findings suggest that CD8(+) T cells might have a significant role in tumor immunity by expressing CD103 in intratumor regions of bladder urothelial cell carcinoma tissues. Intratumor CD103(+) TILs could potentially serve as a prognostic marker in patients with bladder urothelial cell carcinoma., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: T-box transcription factor 21 (T-bet) is a key lineage-defining transcription factor. The purpose of this study was to verify the relationship between expression in primary tumors and prognosis of breast cancer., Methods: T-protein expression was immunohistochemically detected on surgically-obtained tumor samples of 130 (stage I-III) invasive breast carcinomas from Chinese subjects, who were followed up for a mean time of 112 months., Results: T-bet was expressed in the nuclei and cytoplasm of both tumor cells and tumor-infiltrating lymphocytes. In LOG-RANK analysis, higher density of interstitial T-bet+ interstitial lymphocytes was related with longer distant disease-free survival (DDFS) (P = 0.047); higher tumor nuclei T-bet expression was related with shorter DFS (P = 0.021) and DDFS (P = 0.026). Cox multivariate analysis showed that density of interstitial T-bet+ interstitial lymphocytes was an independent positive prognostic factor for DFS (HR = 0.474, P = 0.051) and DDFS (HR = 0.414, P = 0.030); tumor nuclei CTLA-4 expression was an independent adverse prognostic factor for DFS (HR = 3.007, P = 0.003), DDFS (HR = 2.931, P = 0.005) and OS (HR = 2.352, P = 0.029)., Conclusions: This study found that, high tumor nuclei T-bet expression in primary tumors of breast cancer was correlated with poor prognosis and high density of T-bet+ interstitial lymphocytes in primary tumors of breast cancer were correlated with favorable prognosis.

Aim: To investigate the impact of different anesthetic techniques on T-helper (Th) cell subsets in hepatocellular carcinoma (HCC) patients undergoing hepatectomy., Methods: Sixty-one HCC patients who received hepatectomies were randomized into an epidural combined general anesthesia (G + E; n = 31) or a general anesthesia (G; n = 30) group. Blood samples were obtained the morning before the operation (d0), and on the second (d2) and seventh (d7) day after the operation. Th cell contents were evaluated using flow cytometry, real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay., Results: In all 61 patients, Th1 and Th2 cell frequencies, and interferon-γ (IFN-γ) mRNA expression markedly increased on d2, compared to d0. They recovered slightly on d7, and the Th1/Th2 ratio increased markedly on d7, compared with d2. In contrast, Th17, regulatory T cell (Treg), and interleukin-17 (IL-17) levels and FOXP3 mRNA expression showed no significant change on d2, and then markedly decreased on d7. Similarly, plasma IFN-γ concentration on d2 was much higher than that on d0, and then partly recovered on d7. As compared with the G group, in the G + E group, Th1 cell frequencies and the Th1/Th2 ratio were slightly higher on d2 and significantly higher on d7, while Th2, Th17, and Treg cell frequencies were slightly lower on d2, and significantly lower on d7. Consistently, on d7, IFN-γ mRNA and protein levels and the IFN-γ/IL-4 ratio in the G + E group were higher than those in the G group. In contrast, the IL-17 mRNA level, and IL-17 and transforming growth factor-β₁ concentrations in the G + E group were lower than those in the G group., Conclusion: G + E is superior to G in shifting the Th1/Th2 balance towards Th1, while decreasing Th17 and Treg, potentially benefiting HCC patients by promoting anti-tumor Th polarization.

Background and Aim: A new subset of Treg cells, CD4(+) CD69(+) CD25(-) T cells, has been identified in mice. Herein, we aimed to identify this subset of T cells and to evaluate its function in patients with hepatocellular carcinoma (HCC)., Methods: We detected CD4(+) CD69(+) CD25(-) T cells and its expression of CCR6 and transforming growth factor-β1 (TGF-β1) in peripheral blood of 91 HCC patients, 38 chronic hepatitis patients and 34 healthy donors by flow cytometry. CD4(+) CD69(+) CD25(-) T cells in HCC tissues were also analyzed., Results: CD4(+) CD69(+) CD25(-) T cells were significantly increased in peripheral blood of HCC patients compared with healthy persons and chronic hepatitis patients (8.74% ± 0.42% vs 4.55% ± 0.33% and 5.15% ± 0.36%, P < 0.0001). The percentage of peripheral CD4(+) CD69(+) CD25(-) T cells was significantly higher in HCC patients with Tumor Node Metastasis (TNM) stage III plus IV (P < 0.05). Patients with large tumor size and tumor vascular invasion were inclined to obtain high percentage of CD4(+) CD69(+) CD25(-) T cells (P < 0.05). The frequency of membrane-bound TGF-β1 positive cells in CD4(+) CD69(+) CD25(-) T cells from HCC patients was higher than that from the other two groups (P < 0.0001). A considerable proportion of CD4(+) CD69(+) CD25(-) T cells were present in HCC tissues, which has significant correlation with tumor size and TNM stage. Few CD4(+) CD69(+) CD25(-) T cells express CCR6 both in peripheral blood and tumor tissues from HCC patients., Conclusions: Increased CD4(+) CD69(+) CD25(-) T cells in HCC patients are significantly correlated with tumor size, vascular invasion and TNM stage. Thus, increased CD4(+) CD69(+) CD25(-) T cells exert a critical role in HCC progression and might be a clinically aggressive phenotype of HCC., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Transforming growth factor beta 1 (TGF-β1) is a multifunctional cytokine that has been implicated in the oncogenesis and tumour progression. However, the association of TGF-β1 polymorphism with gastric cardia adenocarcinoma (GCA) remains unclear. The aim of the study was to investigate the possible association of the polymorphisms of TGF-β1 with susceptibility to GCA in a population of north China. A case-control analysis was performed to assess the association of six single nucleotide polymorphisms (SNPs) of TGF-β1 and GCA risk. The genotype and allele distributions of TGF-β1 G-800A, C-988A, G915C and C788T in GCA patients were not significantly different from that in healthy controls (P>0.05). The -509T and 869C allele significantly elevated the risk of developing GCA (adjusted OR=1.45 and 1.41; 95% CI=1.04-2.10 and 1.07-2.08, respectively). The CT and TT genotype of C-509T and the TC and CC genotype of T869C significantly elevated the risk of developing GCA. When stratified by tumour stage, the -509T and 869C allele carriers had an increased risk of TNM stage III+IV GCA as compared with noncarriers. The C-509T and T869C SNP are in a strong linkage disequilibrium (D'=0.94). Compared with C/T haplotype, T/C haplotype significantly increased the risk of developing GCA. The TGF-β1 level and expression were higher in GCA patients with -509T or 869C allele than in those without T or C allele (P<0.05). GCA patients with -509TT and 869CC genotype had higher apoptotic tumour-infiltrating lymphocytes in their cancer tissues than those with -509CC and 869TT genotype. In all, TGF-β1 C-509T and T869C polymorphisms may be associated with an increased risk of GCA in north China., (© 2011 Blackwell Publishing Ltd.)