Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during melanoma tumorigenesis

Tamer B. Shabaneh, Aleksey K. Molodtsov, Shannon M. Steinberg, Peisheng Zhang, Gretel M. Torres, Gadisti A. Mohamed, Andrea Boni, Tyler J. Curiel, Christina V. Angeles, Mary Jo Turk

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 FoxP3þ 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.

Original languageEnglish (US)
Pages (from-to)5038-5049
Number of pages12
JournalCancer Research
Volume78
Issue number17
DOIs
StatePublished - Sep 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Oncogenic BRAF<sup>V600E</sup> Governs Regulatory T-cell Recruitment during melanoma tumorigenesis'. Together they form a unique fingerprint.

Cite this