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

作者：Jason J. Luke, Riyue Bao, Randy F. Sweis, Stefani Spranger, Thomas F. Gajewski · 发表于：Clinical Cancer Research · 年份：2019 · DOI：10.1158/1078-0432.ccr-18-1942 · 被引用次数：728 · 研究领域：Wnt/β-catenin signaling in development and cancer、Immunotherapy and Immune Responses、Melanoma and MAPK Pathways

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 mutatio...