A subset of melanoma patients has evidence for spontaneous anti-tumor immune responses and T cell infiltration into tumor sites, which has important prognostic value and is associated with clinical responses to immunotherapies. However, the molecular mechanisms explaining absence of a T cell response in the majority of patients are not defined. Analyses of human melanoma metastases by exome sequencing, gene expression profiling, and IHC have revealed that many tumors that lack a T cell signature show alterations in the Wnt/β-catenin signaling pathway. To investigate if constituently active β-catenin signaling within the tumor cells might inhibit immune responses, we utilized an inducible autochthonous mouse melanoma model driven by inducible BrafV600E and PTEN-deletion, with or without inducible expression of active β-catenin. While Braf/PTEN melanomas showed presence of a modest T cell infiltrate, T cells were nearly completely eliminated in tumors expressing active β-catenin. The T cells that were present in the Braf/PTEN tumors showed an exhausted phenotype as what has been seen in transplanted tumor models, and therapeutic efficacy of combination therapy using αCTLA4 with αPD-L1 mAbs was limited to Braf/PTEN tumors. To test whether the lack of T cell infiltration was due to a defect in early T cell priming, these mice were additionally bred to inducibly express the SIY model antigen within the developing tumors. Adoptive transfer of 2C TCR Tg SIY-specific T cells revealed defective spontaneous T cell priming when tumors expressed active β-catenin. Analysis of the antigen-presenting cell compartment revealed a selective decrease in the CD103+ DC subset within the tumor microenvironment, and T cell infiltration could be restored by intra-tumoral injection of FLT3-ligand-derived dendritic cells. The lack of CD103+ dermal dendritic cells was associated with reduced expression of the chemokines CCL4 and CXCL1. Surprisingly we identified that tumor cells themselves as the major chemokine source in Braf/PTEN tumors, while tumors with active β-catenin signaling lacked expression of those chemokines. Therefore, our data have identified the first defined molecular pathway in tumor cells that results in defective spontaneous anti-tumor T cell responses, an observation with important implications for cancer immunotherapy.
Consent
Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Author information
Authors and Affiliations
Rights and permissions
This article is published under an open access license. Please check the 'Copyright Information' section either on this page or in the PDF for details of this license and what re-use is permitted. If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team.
About this article
Cite this article
Spranger, S., Bao, R. & Gajewski, T. Melanoma-intrinsic β-catenin signaling prevents T cell infiltration and anti-tumor immunity. j. immunotherapy cancer 2 (Suppl 3), O15 (2014). https://doi.org/10.1186/2051-1426-2-S3-O15
Published:
DOI: https://doi.org/10.1186/2051-1426-2-S3-O15