Dataset Information

Tumor-infiltrating podoplanin⁺ cells in gastric cancer: clinical outcomes and association with immune contexture.

ABSTRACT: Podoplanin (PDPN) has been proved to have significant immunoregulatory effects in several types of malignancies and is considered to be a novel immune checkpoint molecule. However, the clinical significance of PDPN and its potential influence on immune contexture in gastric cancer remain obscure. Here, we aimed to investigate the clinical outcomes and immunoregulatory role of tumor-infiltrating PDPN⁺ cells (tPDPNs) in gastric cancer. A total of 454 tumor tissue microarray specimens and 68 fresh tumor tissues of gastric cancer patients from Zhongshan Hospital, and transcriptional data of 293 gastric cancer patients from The Cancer Genome Atlas were included. We demonstrated that tPDPNs high subgroup experienced worse overall survival and disease-free survival, and indicated inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) in gastric cancer. The abundance of tPDPNs was correlated with an immunoevasive contexture characterized by pro-tumor macrophage and dysfunctional CD8⁺ T cell infiltration. Moreover, dysfunctional CD8⁺ T cells in tPDPNs high subgroup exhibited decreased interferon-γ, granzyme B and perforin-1 expression yet elevated programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) expression. Stratification of gastric cancer patients into different risk groups based on tPDPNs and CD8⁺ T cells showed distinct prognosis, responsiveness to ACT and molecular characteristics. This study revealed that the abundance of tPDPNs could identify an immunoevasive contexture and might be applied as an independent predictor for poor prognosis and suboptimal ACT responsiveness. Thus, we recommended tPDPNs as a promising therapeutic target in gastric cancer.

SUBMITTER: Liu X

PROVIDER: S-EPMC7671044 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThe role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC.MethodsThis study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status.ResultsWe observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules.ConclusionCD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

Project description:ImportanceOnly a small fraction of patients with cancer receiving immune checkpoint therapy (ICT) respond, which is associated with tumor immune microenvironment (TIME) subtypes and tumor-infiltrating lymphocytes (TILs).ObjectiveTo examine whether germline variants of natural killer (NK) cells, a key component of the immune system, are associated with TIME subtypes, the abundance of TILs, response to ICT, clinical outcomes, and cancer risk.Design, setting, and participantsThis genetic association study explored TIME subtypes and examined the association of the germline genomic information of patients with cancer with TIME subtypes, abundance of TILs, response to ICT, prognosis, and cancer risk. Clinical information, tumor RNA sequencing, and whole-exome sequencing (WES) data of paired normal samples of patients with 13 common cancers (n = 5883) were obtained from the Cancer Genome Atlas. The WES data of individuals with no cancer (n = 4500) were obtained from the database of Genotypes and Phenotypes. Data collection and analysis took place in March 2017.Main outcomes and measuresAssociations between the number of germline defective genes in NK cells and survival time and the abundance of TILs.ResultsBased on tumor RNA sequencing data, tumors were stratified into TIME-rich, TIME-intermediate, and TIME-poor subtypes. Tumors of TIME-rich subtype had more TILs (TIL-NK cells in TIME-rich head and neck squamous cell carcinoma [HNSC] tumors: t = 4.85; 95% CI of the difference, 0.01-0.03; P = 2.19 × 10-6) compared with TIME-intermediate HNSC tumors (t = 3.70; 95% CI of the difference, 0.01-0.03; P < .001), better prognosis (patients with HNSC: hazard ratio, 0.65; 95% CI, 0.41-1.02; P = .054) compared with TIME-intermediate and TIME-poor subtypes, and better ICT response (patients with melanoma: odds ratio [OR], 4.45; 95% CI, 0.99-27.08; P = .04). Patients with TIME-rich tumors had significantly fewer inherited defective genes in NK cells than patients with TIME-intermediate and TIME-poor tumors (patients with HNSC: OR, 0.49; 95% CI, 0.26-1.07; P = .005). Similarly, patients with cancer had significantly more inherited defective genes in NK cells than individuals with no cancer (patients with HNSC: OR, 19.09; 95% CI, 4.30-315.96; P = 6.21 × 10-4). Among 11 of 13 common cancers, the number of heritable defective genes in NK cells was significantly negatively associated with survival (patients with HNSC: hazard ratio, 1.77; 95% CI, 1.18-2.66; P = .005), abundance of TILs (patients with HNSC: R = -0.25; 95% CI, -0.65-2.17; P = 0.02), and response to ICT (patients with melanoma: OR, 4.45; 95% CI, 0.99-27.08; P = .04).Conclusions and relevanceThese results suggest that individuals who have more inherited defective genes in NK cells had a higher risk of developing cancer and that these inherited defects were associated with TIME subtypes, recruitment of TILs, ICT response, and clinical outcomes. The findings have implications for identifying individuals at risk for developing cancer of many types based on germline variants of NK cells and for improving existing ICT and chimeric antigen receptor-T cell therapy by adoptive transfer of healthy NK cells to patients with TIME-intermediate and TIME-poor tumors.

Dataset Information

Tumor-infiltrating podoplanin⁺ cells in gastric cancer: clinical outcomes and association with immune contexture.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Tumor-infiltrating podoplanin+ cells in gastric cancer: clinical outcomes and association with immune contexture.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Tumor-infiltrating podoplanin⁺ cells in gastric cancer: clinical outcomes and association with immune contexture.