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

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/?-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/?-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in ?-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, and AXIN2; pathway prediction from RNA-sequencing gene expression; and inverse correlation of ?-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 ?-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 ?-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 ?-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased ?-catenin protein levels (20 tumors, 65%). CONCLUSIONS:Activation of tumor-intrinsic WNT/?-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.

SUBMITTER: Luke JJ 

PROVIDER: S-EPMC6522301 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature