Highlights
- •HM tumours fell into three distinct immune subtypes: HM1, HM2 and HM3.
- •HM3 tumours were correlated with CD8 T cell infiltration and prolonged survival.
- •HM2 tumours were correlated with stromal infiltration, EMT and poor outcome.
Abstract
Background
Complete remission is observed in less than half of hypermutated (HM) tumours after
immune checkpoint blockade therapy, indicating that HM tumours are very heterogeneous.
Thus, there is an urgent requirement to decipher the unknown intrinsic HM tumour subtypes.
Methods
Statistical analysis was performed on somatic mutation data from 5519 tumours across
11 cancer types obtained from The Cancer Genome Atlas and 338 colorectal cancer (CRC)
samples obtained from an Asian cohort. Samples with a tumour mutation burden >10 mut/Mb
were classified as HM. A total of 1040 HM samples harbouring corresponding transcriptomes
were used for non-negative matrix factorisation clustering. Tumour mutational burden,
neoantigens, T cell receptor (TCR) diversity, stromal score and immune score were
compared between the subtypes.
Results
HM tumours fell into three distinct immune subtypes: HM1, HM2 and HM3. HM3 tumours
were correlated with increased CD8 T cell infiltration, high TCR diversity, a high
immune score and prolonged survival. HM2 tumours were correlated with an abundant
stromal component, epithelial–mesenchymal transition, TGFβ, angiogenesis hallmarks
and poor outcomes. The infiltration of more CD8 T cells and increased chemokine expression
in HM3 were validated in CRC by immunofluorescence.
Conclusions
These findings will facilitate the development of a subtype-oriented therapy strategy
to enhance the treatment effect in the near future.
Keywords
Abbreviations:
(BCR) (B cell receptor), (BLCA) (bladder urothelial carcinoma), (BRCA) (breast invasive carcinoma), (CESC) (cervical squamous cell carcinoma and endocervical adenocarcinoma), (CRC) (colorectal cancer), (CTLs) (cytotoxic tumour-infiltrating lymphocytes), (DEGs) (differentially expressed genes), (EMT) (epithelial–mesenchymal transition), (FDR) (false discovery rate), (GEO) (Gene Expression Omnibus), (GO) (Gene Ontology), (HM) (hypermutated), (HNSC) (head and neck squamous cell carcinoma), (HR) (hazard ratio), (ICI) (immune checkpoint inhibitor), (INDEL) (insertion and deletion), (ITH) (intratumoural heterogeneity), (KEGG) (Kyoto Encyclopedia of Genes and Genomes), (LUAD) (lung adenocarcinoma), (LUSC) (lung squamous cell carcinoma), (MSI-H) (microsatellite instability-high), (MSI-L) (microsatellite instability-low), (MSigDB) (molecular signatures database), (MSS) (microsatellite stable), (Mb) (million bases), (NMF) (non-negative matrix factorisation), (OS) (overall survival), (OV) (ovarian serous adenocarcinoma), (QN) (quantile normalisation), (SKCM) (skin cutaneous melanoma), (SNP) (single nucleotide polymorphism), (STAD) (stomach adenocarcinoma), (TAMs) (Tumour-associated macrophages), (TCGA) (The Cancer Genome Atlas), (TCR) (T cell receptor), (TILs) (tumour-infiltrating lymphocytes), (TIME) (tumour immune microenvironment), (TMB) (tumour mutational burden), (T-SNE) (t-distributed Stochastic Neighbor Embedding), (UCEC) (uterine corpus endometrial carcinoma)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: March 19, 2021
Accepted:
January 29,
2021
Received in revised form:
December 21,
2020
Received:
August 15,
2020
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
