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Intratumoral interleukin-9 delineates a distinct immunogenic class of gastric cancer patients with better prognosis and adjuvant chemotherapeutic response.

ABSTRACT: Interleukin-9 (IL-9) is a T cell cytokine that is associated with inflammation and allergy, but the expression level of IL-9 in gastric cancer and its clinical significance are less well established. Our study aims to uncover the critical role of IL-9 in the progression of gastric cancer. Here, a total of 453 patients with gastric cancer undergoing curative resection were enrolled for immunohistochemical analyses, and Kaplan-Meier analysis was conducted to compare overall survival of patients in different subgroups. We further investigated the correlation between IL-9 expression and functional status of intratumoral CD8⁺ T cells by means of Flow cytometry. Moreover, in vitro study was preformed to further explore the influence of IL-9 on anti-tumor immunity. Results indicated that gastric cancer patients with high IL-9 expression showed improved overall survival and gained more benefit from 5-fluorouracil-based adjuvant chemotherapy (ACT). High IL-9 expression was associated with increased numbers and elevated function of intratumoral CD8⁺ T cells. In vitro study revealed that recombinant human IL-9 (rhIL-9) exhibit anti-tumor activity via enhancing the function of intratumoral CD8⁺ T cells. Moreover, we found rhIL-9 could augment the efficacy of Pembrolizumab in gastric cancer. In summary, these results suggest that IL-9 expression could act as an independent predictor for overall survival and ACT response and enhancing IL-9 signaling might represent an important therapeutic strategy in gastric cancer.

SUBMITTER: Fang H

PROVIDER: S-EPMC7738302 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceLoss of O6-methylguanine-DNA methyltransferase (MGMT) protein expression has been reported in several malignant tumors and predicts dismal survival outcomes. In gastric cancer, existing studies on this topic are limited and the association between MGMT and fluorouracil-based adjuvant chemotherapy remains obscure.ObjectiveTo investigate the postoperative prognostic significance of MGMT in patients with resectable gastric cancer and its responsiveness to fluorouracil-based adjuvant chemotherapy.Design, setting, and participantsThis study recruited 445 consecutive patients with resectable gastric cancer who underwent radical gastrectomy between August 1, 2007, and December 30, 2008, at Zhongshan Hospital at Fudan University in Shanghai, China. Patients were randomly divided into a discovery data set (n = 200) and a validation data set (n = 245), and the range of follow-up time was from 2 to 76 months for the discovery group and 2 to 79 months for the validation group. The immunoreactivity for MGMT in cancer cells was reviewed under a light microscope by 2 pathologists who were blinded to the clinicopathological data. The association of MGMT expression with clinicopathological characteristics and measures and prognosis was inspected. Data and specimens were collected from patients from the date of surgery to April 25, 2014. Data analysis took place from May 9, 2016, to July 15, 2016.Main outcomes and measuresEstimates of overall survival on the basis of MGMT expression and hazard ratio (HR) for estimates of overall mortality risk.ResultsOf the 445 patients included in the study, 315 (70.8%) were men, and the mean (SD) age of all patients was 60 (12) years. Positive expression of MGMT indicated better overall survival for patients with stage II or III gastric cancer in both the discovery data set (HR, 0.52; 95% CI, 0.32-0.84; P = .003) and the validation data set (HR, 0.63; 95% CI, 0.43-0.93; P = .01). Multivariate analysis identified MGMT expression and TNM stage as 2 independent prognostic factors for overall survival. In stage II disease, the benefit from fluorouracil-based adjuvant chemotherapy was superior among MGMT-positive patients (HR, 0.35; 95% CI, 0.13-0.95; P = .007 for interaction) compared with MGMT-negative patients.Conclusions and relevancePositive expression of MGMT in gastric cancer was identified as an independent, favorable prognostic factor. Incorporating MGMT expression into the current TNM staging system could lead to better prognostic accuracy. These findings should be confirmed within the framework of randomized clinical trials associated with genomic DNA sequencing studies.

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Intratumoral interleukin-9 delineates a distinct immunogenic class of gastric cancer patients with better prognosis and adjuvant chemotherapeutic response.

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