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

Yasuyoshi Sato, Ikuo Wada, Kosuke Odaira, Akihiro Hosoi, Yukari Kobayashi, Koji Nagaoka, Takahiro Karasaki, Hirokazu Matsushita, Koichi Yagi, Hiroharu Yamashita, Masashi Fujita, Shuichi Watanabe, Takashi Kamatani, Fuyuki Miya, Junichi Mineno, Hidewaki Nakagawa, Tatsuhiko Tsunoda, Shunji Takahashi, Yasuyuki Seto, Kazuhiro Kakimi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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 on histological or molecular subtyping of gastric cancer. Molecular and immunological classifications complement each other to predict the responses to anti-PD-1 therapy and have the potential to be a biomarker for the treatment of gastric cancer. Conclusion: The immunological classification of gastric cancer resulted in four subtypes. Hot tumors were further divided into two subtypes, between which the functional status of T cells was different.

Original languageEnglish
Article numbere1194
JournalClinical and Translational Immunology
Volume9
Issue number10
DOIs
Publication statusPublished - 2020
Externally publishedYes

Keywords

  • gastric cancer
  • immunogram
  • RNA-Seq
  • T-cell function
  • tumor immunity

ASJC Scopus subject areas

  • Nursing(all)
  • Immunology and Allergy
  • Immunology

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