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Clin Cancer Res. 2019 May 15;25(10):3074-3083. doi: 10.1158/1078-0432.CCR-18-1942. Epub 2019 Jan 11.

WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers.

Author information

1
Department of Medicine, The University of Chicago, Chicago, Illinois.
2
Center for Research Informatics, The University of Chicago, Chicago, Illinois.
3
Department of Pediatrics, The University of Chicago, Chicago, Illinois.
4
Department of Pathology, The University of Chicago, Chicago, Illinois.
5
Department of Medicine, The University of Chicago, Chicago, Illinois. tgajewsk@medicine.bsd.uchicago.edu.

Abstract

PURPOSE:

The T-cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade, whereas non-T-cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/β-catenin signaling mediates immune exclusion in melanoma, but association with the non-T-cell-inflamed tumor microenvironment in other tumor types is not well understood.

EXPERIMENTAL DESIGN:

Using The Cancer Genome Atlas (TCGA), a T-cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/β-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in β-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, and AXIN2; pathway prediction from RNA-sequencing gene expression; and inverse correlation of β-catenin protein levels with the T-cell-inflamed gene expression signature.

RESULTS:

Across TCGA, 3,137/9,244 (33.9%) tumors were non-T-cell-inflamed, whereas 3,161/9,244 (34.2%) were T-cell-inflamed. Non-T-cell-inflamed tumors demonstrated significantly lower expression of T-cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of β-catenin signaling molecules in non-T-cell-inflamed tumors were enriched three-fold relative to T-cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated β-catenin signaling in the non-T-cell-inflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of β-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased β-catenin protein levels (20 tumors, 65%).

CONCLUSIONS:

Activation of tumor-intrinsic WNT/β-catenin signaling is enriched in non-T-cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy.See related commentary by Dangaj et al., p. 2943.

PMID:
30635339
PMCID:
PMC6522301
[Available on 2020-05-15]
DOI:
10.1158/1078-0432.CCR-18-1942
[Indexed for MEDLINE]

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