Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 10, Pages 3074-3083Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-1942
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Funding
- U.S. Department of Defense Career Development Award [W81XWH-17-1-0265]
- Arthur J. Schreiner Family Melanoma Research Fund
- J. Edward Mahoney Foundation Research Fund
- Brush Family Immunotherapy Research Fund
- Buffet Fund for Cancer Immunotherapy
- Center for Research Informatics by the Biological Sciences Division at The University of Chicago
- Institute for Translational Medicine/Clinical and Translational Award [NIH 5UL1TR002389-02]
- University of Chicago Comprehensive Cancer Center Support Grant [NIH P30CA014599]
- American Cancer Society-Jules L. Plangere Jr. Family Foundation Professorship in Cancer Immunotherapy
- NIH [R35 CA210098]
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Purpose: The T-cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade, whereas non-T-cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/beta-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/beta-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in beta-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, and AXIN2; pathway prediction from RNA-sequencing gene expression; and inverse correlation of beta-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 beta-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 beta-catenin signaling in the non-T-cellinflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of b-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased b-catenin protein levels (20 tumors, 65%). Conclusions: Activation of tumor-intrinsic WNT/beta-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.
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