Abstract 4006: Immune cell profiles and β-catenin signaling in melanoma
Authors: Jeremie Nsengimana, Sathya Muralidhar, Joanna Pozniak, Jon P. Laye, D T. Bishop, Julia A. Newton-Bishop
Journal: Cancer Research (2017)

Abstract Introduction Immune profiling is a necessary step in understanding tumor microenvironment and predicting the response to immunotherapies. Methods We used the expression of genes exclusively expressed by immune cells in tumors1, to classify 703 formalin-fixed primary melanomas from the Leeds Melanoma Cohort. Transcriptomes were generated from tumor cores using Illumina DASL HT 12.4 array. In the obtained tumor subgroups with differing immune profiles, we tested the hypothesis that β-catenin signaling controls immune suppression in primary tumors as earlier reported in vitro and murine data2. Results We found and validated 6 tumor classes, which showed consistency with other published gene signatures, and predicted melanoma-specific survival (HR=1.8, P=0.003, adjusted for AJCC stage, site, age, sex, ulceration, mitotic rate, BRAF/NRAS mutation). Tumors of good prognosis expressed markedly a large number of markers of T cell cytotoxicity, dendritic cells, macrophages, NK CD56 dim cells and genes coding for checkpoint co-inhibitor molecules (Table 1). They also had upregulation of β-catenin suppressors3 and downregulated β-catenin itself (Table 1). By contrast, poor prognosis tumors (the largest group) lacked both innate and adaptive immunity, and had activation of canonical β-catenin signaling (CTNNB1, its targets and WNT receptors) and WNT-independent β-catenin signaling (Table 1). Conclusion In a large subset of this population-based cohort of primary tumors, we report evidence of immune evasion through β-catenin signaling pathway. These results obtained from archival material suggest that transcriptomic profiling is a viable alternative to flow cytometry in understanding tumor biology and in determining the effectiveness of immunotherapies. Table 1.Immune scores and β-catenin signaling in good/bad prognosis groupsGene expression derived characteristicGood prognosisBad prognosis A. Immune scores from gene expressionCytotoxic T cell (e.g. GZMA, GZMH, KLRB1, KILRD1)updownDendritic cells (e.g. CD1B, CCL13, CCL22, IDO1, IDO2)updownNK CD56 dim (e.g. IL21R, GZMB, KIR2DS5, KIR3DL1)updownMacrophages (e.g. PTGDS, GM2A, CD68, SC5, ATG7)updownB. Checkpoint moleculesPDL1updownCTLA4updownVISTAupdownTIM3updownLAG3updownBTLAupdownC. β-catenin inhibitorsupdownDKK2 (secreted)updownDKK3 (secreted)updownSFRP2 (secreted)updownAXIN2 (intracellular)updownNKD2 (intracellular)updownD. β-catenin, its targets and WNT receptorsCTNNB1 (β-catenin)downupDVL1, DVL2, DVL3downupTCF12, TCF1downupAPC2, APC,c-MyCdownupFZ5, FZ9downupE. WNT-independent β-catenin signaling FGFR4downupPYGO1downupBCL9downupFOXM1downupNUP98downupSMAD4downup References 1. Bindea et al. 2013. Immunity 39 (4): 782-95. 2. Spranger et al. (2015). Nature 523:231-5. 3. MacDonald et al. (2009). Developmental Cell 17(1): 9-26. Citation Format: Jeremie Nsengimana, Sathya Muralidhar, Joanna Pozniak, Jon P. Laye, D T. Bishop, Julia A. Newton-Bishop. Immune cell profiles and β-catenin signaling in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4006. doi:10.1158/1538-7445.AM2017-4006