Integrative immunogenomic analysis of gastric cancer dictates novel immunological classification and the functional status of tumor‐infiltrating cells

Abstract

Objectives. A better understanding of antitumor immunity will help predict the prognosis of gastric cancer patients and tailor the appropriate therapies in each patient. Therefore, we propose a novel immunological classification of gastric cancer. Methods. We performed whole-exome sequencing (WES), RNA-Seq and flow cytometry in 29 gastric cancer patients who received surgery. The TCGA data set of 323 gastric cancer patients and RNA-Seq data of 45 patients who received pembrolizumab (Kim et al. Nat Med 2018; 24: 1449-1458) were also analysed. Results. Immunogram analysis of cancer-immunity interaction of gastric cancer revealed immune signatures of four main types, designated Hot1, Hot2, Intermediate and Cold. Immunologically hot tumors displayed a dysfunctional T-cell signature, while cold tumors had an exclusion signature. Ex vivo tumor-infiltrating lymphocyte analysis documented T-cell dysfunction with the expression of checkpoint molecules and impaired cytokine production. The T-cell function was more profoundly damaged in Hot1 than Hot2 tumors. Patients in Hot2 subtypes had better survival in our cohort and TCGA cohort. Although these immunological subtypes overlapped to some degree with the molecular subtypes in the TCGA, intratumoral immune responses cannot be predicted solely based

Two distinct phenotypes of immunologically hot gastric cancer subtypes

“…Complete immune profiling was performed on 29 patients diagnosed with histologically-confirmed gastric cancer at Tokyo Metropolitan Bokutoh Hospital between June 2014 and October 2017, designated the “BKT cohort” [ 10 ]. Clinical profiles with histology by the Lauren classification, macroscopic classification by the Borrmann classification, locus of the primary site, TNM clinical staging, overexpression of human epidermal growth factor receptor 2 (HER2) protein and the presence or absence of Helicobacter pylori infection were reported in our previous work [ 10 ]. These patients' tumors were immunologically classified into Hot 1, Hot 2, Intermediate and Cold subtypes.…”

“…Therefore, immune profiling of gastric cancer and immunological classification were extensively studied [ [6] , [7] , [8] , [9] ]. Previously, we also proposed a novel immunological classification of gastric cancer [ 10 ]. We performed RNA-Seq and analyzed the tumor microenvironment (TME) of gastric cancer in the context of the so-called “cancer-immune cycle” [ 11 ].…”

“…We performed RNA-Seq and analyzed the tumor microenvironment (TME) of gastric cancer in the context of the so-called “cancer-immune cycle” [ 11 ]. We then proposed an “Immunogram Score” classification for gastric cancer [ 10 ]. According to this, gastric cancers were immunologically classified into several types, designated Hot, Intermediate and Cold.…”

“…Novel combination immunotherapy for patients with Hot 1 tumors must be developed, bearing these characteristics in mind. Among 29 RNA-Seq data in our previous study [ 10 ], we focused on 12 RNA-Seq data of patients who were classified in Hot 1 or Hot 2 subtype. We newly re-evaluated the RNA-Seq data of Hot 1 and Hot 2 tumors of same patients to understand the underlying reasons for the poor prognosis of Hot 1 tumors and whether this was indeed associated with T cell dysfunction.…”

Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody

“…For the comprehension of the immunological microenvironment of the tumor, we constructed the immunogram, a scoring system based on RNA-sequence data describing individual cancerimmunity interactions [33][34][35]. We performed single-sample gene set enrichment analysis (ssGSEA) of these 40 tumors with 10 gene sets, innate immunity: natural killer cells (axis 1), priming and activation: dendritic cells (DCs) (axis 2), T cells: CD8 + T-cell response (axis 3), interferon-γ (IFNG) response (axis 4), inhibitory molecules (axis 5), inhibitory cells (regulatory T cells, axis 6), inhibitory cells (myeloid-derived suppressor cells, axis 7), recognition of tumor cells, antigen processing and presentation (axis 8), proliferation (axis 9), and glycolysis (axis 10), as described previously [34].…”