Oncogenic BRAF V600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-09, Vol.78 (17), p.5038
• Main Authors: Shabaneh, Tamer B, Molodtsov, Aleksey K, Steinberg, Shannon M, Zhang, Peisheng, Torres, Gretel M, Mohamed, Gadisti A, Boni, Andrea, Curiel, Tyler J, Angeles, Christina V, Turk, Mary Jo
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Carcinogenesis - genetics; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Lymph Nodes - metabolism; Lymph Nodes - pathology; Melanocytes - immunology; Melanocytes - pathology; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Mice; Mutation; Proto-Oncogene Proteins B-raf - genetics; PTEN Phosphohydrolase - genetics; Receptors, CCR4 - genetics; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumor Microenvironment - genetics
• ISSN: 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-0365

Regulatory T cells (Treg) are critical mediators of immunosuppression in established tumors, although little is known about their role in restraining immunosurveillance during tumorigenesis. Here, we employ an inducible autochthonous model of melanoma to investigate the earliest Treg and CD8 effector T-cell responses during oncogene-driven tumorigenesis. Induction of oncogenic BRAF and loss of Pten in melanocytes led to localized accumulation of FoxP3 Tregs, but not CD8 T cells, within 1 week of detectable increases in melanocyte differentiation antigen expression. Melanoma tumorigenesis elicited early expansion of shared tumor/self-antigen-specific, thymically derived Tregs in draining lymph nodes, and induced their subsequent recruitment to sites of tumorigenesis in the skin. Lymph node egress of tumor-activated Tregs was required for their C-C chemokine receptor 4 (Ccr4)-dependent homing to nascent tumor sites. Notably, BRAF signaling controlled expression of Ccr4-cognate chemokines and governed recruitment of Tregs to tumor-induced skin sites. BRAF expression alone in melanocytes resulted in nevus formation and associated Treg recruitment, indicating that BRAF signaling is sufficient to recruit Tregs. Treg depletion liberated immunosurveillance, evidenced by CD8 T-cell responses against the tumor/self-antigen gp100, which was concurrent with the formation of microscopic neoplasia. These studies establish a novel role for BRAF as a tumor cell-intrinsic mediator of immune evasion and underscore the critical early role of Treg-mediated suppression during autochthonous tumorigenesis. This work provides new insights into the mechanisms by which oncogenic pathways impact immune regulation in the nascent tumor microenvironment. .