Objective: To investigate the clinical significance of IL-10 þ tumor-associated macrophages (TAMs) in gastric cancer. Background: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10 þ TAMs in gastric cancer remains obscure. Methods: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10 þ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model. Results: Gastric cancer patients with high IL-10 þ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10 þ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8 þ T cell dysfunction. The combinational analysis of IL-10 þ TAM and CD8 þ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10 þ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. Conclusions: This study revealed that IL-10 þ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy,indicating IL-10 þ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.
Background: Tumor IL17-producing (IL17A þ) cells infiltration has different prognostic values among various cancers. The objective of this study was to assess the effect of IL17A þ cells in gastric cancer. Patients and methods: The study included two patient cohorts, the Cancer Genome Atlas cohort (TCGA, n ¼ 351) and the Zhongshan Hospital cohort (ZSHC, n ¼ 458). The TCGA and ZSHC were used for mRNA-related and cells infiltration-related analyses, respectively. The roles of IL17A mRNA and IL17A þ cells in overall survival (OS), response to adjuvant chemotherapy (ACT), and immune contexture were evaluated. Another independent cohort was included to identify the correlation between mRNA of IL17A and IL17A þ cells infiltration (the preliminary Zhongshan Hospital cohort, PZSHC, n ¼ 21). Results: The infiltration of IL17A þ cells was positively correlated with the expression of IL17A mRNA (Spearman's q ¼ 0.811; P < 0.001). High IL17A mRNA expression and intratumoral IL17A þ cells were correlated with improved OS and remained to be significant after adjusted for confounders. Patients with TNM II/III disease whose tumor present higher intratumoral IL17A þ cells or lower peritumoral IL17A þ cells can benefit more from ACT. Elevated IL17A mRNA expression and increased intratumoral IL17A þ cells infiltration was associated with more antitumor mast cells and nature killer cells infiltration and less pro-tumor M2 macrophages infiltration. High IL17A mRNA expression represented a Th17 cells signature and immune response process and was correlated with increased cytotoxic GZMA, GZMB, IFNG, PRF1, and TNFSF11 expression. Conclusions: IL17A mRNA expression and intratumoral IL17A þ cells infiltration were correlated with antitumor immune contexture. IL17A þ cells infiltration could be used as an independent prognostic biomarker for OS and predictive biomarker for superior response to ACT, and further prospective validation needs to be conducted.
Studies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.
Apolipoprotein B mRNA editing enzyme catalytic polypeptide 3B (APOBEC3B) plays an important role in tumor mutagenesis. However, its clinical significance in gastric cancer (GC) remains largely unknown. We enrolled a total of 482 GC patients from Zhongshan Hospital, Fudan University for immunohistochemistry (IHC) staining to evaluate the prognostic and predictive values of APOBEC3B. Genomic and phenotypic datasets from the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohort were downloaded for external validation and complementary bioinformatic analysis. Fresh specimens of additional 60 patients from Zhongshan Hospital, Fudan University were collected to detect CD8 + T cell phenotype with flow cytometry (FCM). The high expression of APOBEC3B indicated inferior overall survival (OS, P < .001 and P = .003) and disease-free survival (DFS, P < .001 and P < .001), yet superior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) in TNM stage II patients. The tumor microenvironment (TME) of APOBEC3B-enriched tumors was characterized by reduced infiltration of tumor reactive CD8 + T cells expressing both effector molecules and immune checkpoints. APOBEC3B high CD8 + T cell high GC patients were most likely to benefit from ACT and PD-1 blockade. Our study demonstrates that APOBEC3B was an independent prognostic and predictive factor in GC. The potential interplay between APOBEC3B and CD8 + T cells merited further investigations.
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