Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens

Takamasa Ishino, Shusuke Kawashima, Etsuko Tanji, Toshihide Ueno, Youki Ueda, Sadahisa Ogasawara, Kazuhito Sato, Hiroyuki Mano, Soichiro Ishihara, Naoya Kato, Masahito Kawazu, Yosuke Togashi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Background: Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME). Methods: We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets. Results: We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types. Conclusions: We propose a novel concept of “paradoxical neoantigenic mutations” that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1166-1175
Number of pages10
JournalBritish Journal of Cancer
Volume128
Issue number6
DOIs
Publication statusPublished - Apr 6 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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