Genetic and immune landscape evolution in MMR-deficient colorectal cancer
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The Journal of Pathology - 2023 ...
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Authors
Challoner, BRWoolston, A
Lau, D
Buzzetti, M
Fong, C
Barber, LJ
Anandappa, G
Crux, R
Assiotis, I
Fenwick, K
Begum, R
Begum, D
Lund, T
Sivamanoharan, N
Sansano, HB
Domingo-Arada, M
Tran, A
Pandha, H
Church, D
Eccles, B
Ellis, R
Falk, S
Hill, M
Krell, D
Murugaesu, N
Nolan, L
Potter, V
Saunders, Mark
Shiu, KK
Guettler, S
Alexander, JL
Lázare-Iglesias, H
Kinross, J
Murphy, J
von Loga, K
Cunningham, D
Chau, I
Starling, N
Ruiz-Bañobre, J
Dhillon, T
Gerlinger, M
Affiliation
The Christie NHS Foundation Trust, Manchester, UK.Issue Date
2023
Metadata
Show full item recordAbstract
Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β-catenin, mitogen-activated protein kinase, and TGF-β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Citation
Challoner BR, Woolston A, Lau D, Buzzetti M, Fong C, Barber LJ, et al. Genetic and immune landscape evolution in MMR-deficient colorectal cancer. J Pathol. 2023 Nov 15. PubMed PMID: 37964706. Epub 2023/11/15. eng.Journal
Journal of PathologyDOI
10.1002/path.6228PubMed ID
37964706Additional Links
https://dx.doi.org/10.1002/path.6228Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1002/path.6228