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.

BACKGROUND: Intratumoural CD103 + CD8 + T cells have been linked to prolonged survival in several malignancies. However, the clinical significance of CD103 + CD8 + T cells in gastric cancer remains unexplored. METHODS: Gastric cancer tissues from Zhongshan Hospital and data from Gene Expression Omnibus were obtained and analysed. Immunohistochemistry and flow cytometry were performed to detect the number and phenotypical characteristics of CD103 + CD8 + T cells. The effect of programmed cell death protein-1 (PD-1) blockade on CD103 + CD8 + T cells was evaluated with the use of an in vitro study based on fresh tumour tissues. RESULTS: CD103 + CD8 + T cells predicted superior overall survival and provided better prognostic power than total CD8 + T cells in gastric cancer. Patients with high CD103 + CD8 + T cell infiltration also gained more benefit from adjuvant chemotherapy. Flow cytometry analysis showed that CD103 + CD8 + T cells exerted superior anti-tumour effects with stronger retention capacity and cytotoxicity. Moreover, an in vitro study showed that CD103 + CD8 + T cells were more functionally restored after PD-1 blockade than CD103 -CD8 + T cells. CONCLUSIONS: CD103 + CD8 + T cells might be a useful marker to predict prognosis and therapeutic efficacy for gastric cancer patients. Efforts to increase intratumoural CD103 + CD8 + T cell frequency might be a novel therapeutic strategy in gastric cancer.