Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02293
Keywords
WNT/beta-catenin signaling pathway; T cell-inflammation; tumor microenvironment; CD8(+) T cells; immune exclusion; immunotherapy
Categories
Funding
- National Key Research and Development Program of China [2018YFC1705301]
- NSFC of China [81874470, 81874319]
- Shanghai Development Office of TCM [ZY(2018-2020)-FWTX-1008, ZY(2018-2020)-CCCX-2004-08, ZY(2018-2020)-FWTX-4010]
- Development Fund for Shanghai Talents [2017047]
- Young Talent Supporting Program of the China Association of Traditional Chinese Medicine [CACM-2017-QNRC2-(B05)]
- Science and Technology Commission of Shanghai Municipality [18401933500]
- Shanghai Municipal Education Commission [2019-01-07-00-10-E00072]
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Immunotherapy with checkpoint inhibitors has greatly prolonged the overall survival of cancer patients in melanoma and many other cancer types. However, only a subset of patients shows clinical responses from these interventions, which was predicated by the T cell-inflamed tumor microenvironment. T cell-inflamed phenotype is characterized by the infiltration of CD8(+) T cells, CD8 alpha/CD103-lineage dendritic cells (DCs), as well as high density of forkhead box P3 (FoxP3)(+) regulatory T cells (Tregs) that are associated with the efficacy of immune checkpoint blockade. A number of regulators has been associated with T cell-inflammation in the tumor microenvironment, and WNT/beta-catenin signaling is one of the best characterized. The tumor-intrinsic WNT/beta-catenin signaling activation is frequently associated with poor spontaneous T cell infiltration across most human cancers. In this article, we review the essential roles of WNT/beta-catenin signaling in the T cell-inflamed and non-T cell-inflamed tumor microenvironment, including the development and function of immune cells, activation of immune exclusion of tumor cells, and cancer immunosurveillance. We also discuss the impact of this pathway in driving the non-T cell-inflamed tumor microenvironment in other tumor types. To improve immunotherapy efficacy, we argue that targeting Wnt/beta-catenin signaling should be a high priority for combinational cancer therapy to restore T cell infiltration.
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