Abstract B33: Langerhans cells prevent melanocytic nevus development and transformation in mice.

Abstract

Abstract The function of Langerhans cells (LCs) in the skin immune system is unclear, and a matter of intense debate. In different mouse models LCs have been shown to induce antitumor immunity or promote skin squamous cell carcinoma (SCC). Their role in the control or promotion of melanoma is not known. We assessed LC's role in the development of DMBA-TPA induced pigmented benign and transformed lesions in a novel mouse model. Transgenic HuLang-DTA+/- C57Bl/6 mice, which selectively ablate epidermal LCs, were crossed with C3H/HeN mice to generate F1 LC knockout (KO) and WT littermate controls. LC-KO mice developed 40% more and 2-fold larger melanocytic lesions than WT. Cell suspensions from LC-KO pigmented skin lesions contained increased CD4+ Foxp3+ regulatory T cells and CD11b-/loGr-1hi cells, consistent with an immunosuppressive microenvironment. CD11c+CD11b+Ly6C+ APCs or MHCII+ cell numbers were fewer in lesions from LC-KO as compared to WT mice. Nests of melanocytic cells were observed at a higher frequency in draining lymph nodes (dLNs) from LC-KO as compared to WT; DLN cells contained increased numbers of TRP2+ cells and routinely gave rise to proliferative melanocytic cell lines. Real-time PCR analysis of epidermal cDNA from TPA treated LC-KO, as compared to WT, demonstrated a profound loss of IL-10, IL-12p35 and IL-12p40, indicating LCs as the major source. Further, IL-23 steady state levels in the epidermis of LC-KO are increased greater than 3-fold over WT, indicating that LCs normally suppress keratinocyte production of IL-23. Thus, in contrast to SCC, LCs inhibit development of benign and metastatic pigmented tumors. This novel murine model will be useful in elucidating transformation mechanisms and identifying novel therapeutic targets that may prevent metastatic melanoma. Citation Format: Tahseen H. Nasti, Yuko Tsuruta, Kris McKay, Mohammad Athar, Craig Elmets, Laura Timares. Langerhans cells prevent melanocytic nevus development and transformation in mice.. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B33. doi:10.1158/1538-7445.CHTME14-B33