Tumor Immune Microenvironment and Chemosensitivity Signature for Predicting Response to Chemotherapy in Gastric Cancer

Abstract

Current gastric cancer staging alone cannot predict prognosis and adjuvant chemotherapy benefits in stage II and III gastric cancer. Tumor immune microenvironment biomarkers and tumor-cell chemosensitivity might add predictive value to staging. This study aimed to construct a predictive signature integrating tumor immune microenvironment and chemosensitivity-related features to improve the prediction of survival and adjuvant chemotherapy benefits in patients with stage II to III gastric cancer. We used IHC to assess 26 features related to tumor, stroma, and chemosensitivity in tumors from 223 patients and evaluated the association of the features with disease-free survival (DFS) and overall survival (OS). Support vector machine (SVM)-based methods were used to develop the predictive signature, which we call the SVM signature. Validation of the signature was performed in two independent cohorts of 445 patients. The diagnostic signature integrated seven features: CD3⁺ cells at the invasive margin (CD3 IM), CD8⁺ cells at the IM (CD8 IM), CD45RO⁺ cells in the center of tumors (CD45RO CT), CD66b⁺ cells at the IM (CD66b IM), CD34⁺ cells, periostin, and cyclooxygenase-2. Patients fell into low- and high-SVM groups with significant differences in 5-year DFS and OS in the training and validation cohorts (all P < 0.001). The signature was an independent prognosis indicator in multivariate analysis in each cohort. The signature had better prognostic value than various clinicopathologic risk factors and single features. High-SVM patients exhibited a favorable response to adjuvant chemotherapy. Thus, this SVM signature predicted survival and has the potential for identifying patients with stage II and III gastric cancer who could benefit from adjuvant chemotherapy.