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Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis
- Source :
- Cancer Research. 78:5038-5049
- Publication Year :
- 2018
- Publisher :
- American Association for Cancer Research (AACR), 2018.
-
Abstract
- 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 BRAFV600E 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, BRAFV600E signaling controlled expression of Ccr4-cognate chemokines and governed recruitment of Tregs to tumor-induced skin sites. BRAFV600E expression alone in melanocytes resulted in nevus formation and associated Treg recruitment, indicating that BRAFV600E 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 BRAFV600E as a tumor cell–intrinsic mediator of immune evasion and underscore the critical early role of Treg-mediated suppression during autochthonous tumorigenesis. Significance: This work provides new insights into the mechanisms by which oncogenic pathways impact immune regulation in the nascent tumor microenvironment. Cancer Res; 78(17); 5038–49. ©2018 AACR.
- Subjects :
- Proto-Oncogene Proteins B-raf
0301 basic medicine
Cancer Research
Receptors, CCR4
Carcinogenesis
Regulatory T cell
chemical and pharmacologic phenomena
CD8-Positive T-Lymphocytes
Biology
T-Lymphocytes, Regulatory
Article
Mice
03 medical and health sciences
Chemokine receptor
0302 clinical medicine
Melanocyte differentiation
Antigens, Neoplasm
Cell Line, Tumor
Tumor Microenvironment
medicine
Animals
Humans
Cytotoxic T cell
Melanoma
Tumor microenvironment
PTEN Phosphohydrolase
FOXP3
hemic and immune systems
medicine.disease
Gene Expression Regulation, Neoplastic
Immunosurveillance
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Mutation
Cancer research
Melanocytes
Lymph Nodes
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 78
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....02b17427df223f459c9e86d77e92eb9f