Clinical impact of tumor-infiltrating CD45RO+ memory T cells on human gastric cancer

BackgroundCD4+ memory T cells are an important component of the tumor microenvironment (TME) and affect tumor occurrence and progression. Nevertheless, there has been no systematic analysis of the effect of CD4+ memory T cells in gastric cancer (GC).MethodsThree datasets obtained from microarray and the corresponding clinical data of GC patients were retrieved and downloaded from the Gene Expression Omnibus (GEO) database. We uploaded the normalize gene expression data with standard annotation to the CIBERSORT web portal for evaluating the proportion of immune cells in the GC samples. The WGCNA was performed to identify the modules the CD4+ memory T cell related module (CD4+ MTRM) which was most significantly associated with CD4+ memory T cell. Univariate Cox analysis was used to screen prognostic CD4+ memory T cell-related genes (CD4+ MTRGs) in CD4+ MTRM. LASSO analysis and multivariate Cox analysis were then performed to construct a prognostic gene signature whose effect was evaluated by Kaplan-Meier curves and receiver operating characteristic (ROC), Harrell’s concordance index (C-index), and decision curve analyses (DCA). A prognostic nomogram was finally established based on the CD4+ MTRGs.ResultWe observed that a high abundance of CD4+ memory T cells was associated with better survival in GC patients. CD4+ MTRM was used to stratify GC patients into three clusters by unsupervised clustering analysis and ten CD4+ MTRGs were identified. Overall survival, five immune checkpoint genes and 17 types of immunocytes were observed to be significantly different among the three clusters. A ten-CD4+ MTRG signature was constructed to predict GC patient prognosis. The ten-CD4+ MTRG signature could divide GC patients into high- and low-risk groups with distinct OS rates. Multivariate Cox analysis suggested that the ten-CD4+ MTRG signature was an independent risk factor in GC. A nomogram incorporating this signature and clinical variables was established, and the C-index was 0.73 (95% CI: 0.697–0.763). Calibration curves and DCA presented high credibility for the OS nomogram.ConclusionWe identified three molecule subtypes, ten CD4+ MTRGs, and generated a prognostic nomogram that reliably predicts OS in GC. These findings have implications for precise prognosis prediction and individualized targeted therapy.

Download Full-text

Prognostic potential of tumoral FOXP3 expression in relation with tumor-infiltrating regulatory T cells in human gastric cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15036 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15036-e15036

Author(s):

Jungho Suh ◽

Wankyu EO ◽

Si-Young Kim

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

T Cells ◽

Regulatory T Cells ◽

Cancer Cells ◽

Prognostic Marker ◽

Prognostic Significance ◽

Foxp3 Expression ◽

Cancer Tissue ◽

Human Gastric Cancer

e15036 Background: Expression of the transcription factor FOXP3 is crucial for the regulatory T cells (Tregs) that engage in the maintenance of immunological self-tolerance and immune homeostasis. Recently, expression of FOXP3 in cancer cells and its association with prognosis have been shown in clinical studies. For gastric cancer, however, prognostic significance of the tumoral FOXP3 expression and its relationship with Tregs remains unknown. We observed the tumoral FOXP3 and Tregs from the 118 gastric cancer patients who underwent surgery to explore its relationships with the prognosis. Methods: Tissue samples from 118 cases of gastric cancer were used for the present study. We investigated the tumoral expression of FOXP3 and Tregs count in human gastric cancer tissue by the use of immunohistochemical analysis using a tissue microarray to explore the relation with clinicopathological variables by retrospective manner. Results: FOXP3-positive cancer cells were observed in 62 of 118 (52.5%) patients. Positive Tregs (Tregs≥10/HPF) were observed in 66 of 118 (55.9%) patients. There was significant positive relationship between positive Tregs count and the tumoral FOXP3 expression (P=0.006).Positive tumoral FOXP3 expression was significantly related with the better disease free survival but not with the overall survival. But increased Tregs count was significantly related with the better overall survival (P<0.01, P<0.01, respectively). When we divide the patients into four groups by the FOXP3 expression and the Tregs count, FOXP3/Tregs(+/+) group showed the best overall survival followed by FOXP3/Tregs(-/+) group, FOXP3/Tregs(+/-,) and FOXP3/Tregs(-/-), respectively. And the survival difference between the FOXP3/Tregs(+/+)-FOXP3/Tregs(-/+) group and the FOXP3/Tregs(+/-)-FOXP3/Tregs(-/-)group became more prominent by the Tregs count. Conclusions: These results suggest that positive tumoral FOXP3 expression in relation with the high Treg count is a new prognostic marker in gastric cancer. The combination of tumoral FOXP3 and Tregs enhanced its statistical power more than separated as a prognostic marker.

Download Full-text

Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

Cellular Physiology and Biochemistry ◽

10.1159/000493110 ◽

2018 ◽

Vol 49 (2) ◽

pp. 828-836 ◽

Cited By ~ 10

Author(s):

Wang Ping ◽

Hu Senyan ◽

Gu Li ◽

Chen Yan ◽

Lu Long

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Lactate Dehydrogenase ◽

Immune Function ◽

Cell Function ◽

Lactate Concentration ◽

Tumor Infiltrating Lymphocytes ◽

Clinical Samples ◽

Human Gastric Cancer ◽

Cancer Tumor

Background/Aims: Lactate is one of the products of glycolysis and is a hallmark of the Warburg effect. Glycolysis is found in tumor as well as immune cells. However, the effects of lactate on the function of tumor-infiltrating T cells (TILs) are rarely reported. Methods: In the present study, we investigated lactate and other glycolysis-related metabolites within TILs of human gastric cancer (GC). Lactate concentration was determined by liquid chromatography–mass spectrometry. The functional effects and clinical relevance of excessive lactate on T cells were investigated in clinical samples, and the mechanism of increased lactate was explored. Results: Lactate was significantly increased in GC TILs and related to decreased T helper (Th)1 cells and cytotoxic T lymphocytes (CTLs). Increased lactate within GC TILs was positively correlated with increased lactate dehydrogenase A (LDH)A. Expression of LDHA in GC TILs was also negatively correlated with percentages of Th1 cells and CTLs. Decreased miR-34a expression in GC TILs was responsible for increased expression of LDHA. A hypoxic tumor environment was responsible for decreased miR-34a and lactate-induced impaired immune function. Conclusion: We found that hypoxia decreases miR-34a expression and lose miR-34a regulation on LDHA, thus increasing lactate level within GC TILs and impairing immune function in GC.

Download Full-text

Clinical efficacy of nivolumab is associated with tertiary lymphoid structures in surgically resected primary tumors of recurrent gastric cancer

PLoS ONE ◽

10.1371/journal.pone.0262455 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0262455

Author(s):

Takuya Mori ◽

Hiroaki Tanaka ◽

Sota Deguchi ◽

Yoshihito Yamakoshi ◽

Yuichiro Miki ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Memory T Cells ◽

Tissue Samples ◽

Primary Tumors ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Third Line ◽

Resident Memory T Cells ◽

Better Than

Nivolumab, an immune checkpoint blocker, has been approved for advanced gastric cancer (GC), but predictive factors of nivolumab’s efficacy in patients with GC, especially immune cells such as tissue-resident memory T cells or those forming tertiary lymphoid structures (TLS), remain unclear. Tissue samples were obtained from surgically resected specimens of patients with GC who were treated with nivolumab as third-line or later treatment. Immunohistochemical staining was performed to detect the presence of TLS and CD103+ T cells and assess the association between TLSs and response to nivolumab treatment. A total of 19 patients were analyzed. In patients with partial response (PR) to nivolumab, numerous TLS were observed, and CD103+ T cells were found in and around TLS. Patients with many TLS experienced immune-related adverse events more often than those with few TLS (p = 0.018). The prognosis of patients with TLS high was better than those with TLS low. Patients with a combination of TLS high and CD103 high tended to have a better prognosis than other groups. Our results suggested that TLS status might be a predictor of nivolumab effectiveness.

Download Full-text