Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 3, Issue -, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1186/s40425-015-0089-6
Keywords
Tumor microenvironment; Immune evasion; Checkpoint inhibition; T-cell infiltration
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Funding
- Team Science Award from the Melanoma Research Alliance
- Cancer Research Institute Translational Research Award
- Cancer Research Institute Irvington Postdoctoral Fellowship
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Increasing evidence is emerging that immunotherapeutic interventions, including checkpoint blockade, are predominantly effective in patients with a pre-existing T cell-inflamed tumor microenvironment. Understanding the mechanisms leading to a non-T cell-inflamed microenvironment are crucial for the development of novel treatment modalities to expand the fraction of patients benefiting from immunotherapy. Based on the hypothesis that one source of inter-patient heterogeneity would lie at differential activation of specific oncogene pathways within the tumor cells themselves, our group recently observed that tumor-cell intrinsic activation of the WNT/beta-catenin pathway correlates with absence of T cells from the microenvironment in metastatic melanoma. Genetically-engineered mouse models confirmed a causal relationship, via a mechanism of failed Batf3-lineage dendritic cell recruitment. Hence, tumor cell-intrinsic activation of beta-catenin is the first oncogenic pathway demonstrated to exclude the anti-tumor immune response, revealing a potential therapeutic target for improving immunotherapy responsiveness.
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