TY - JOUR
T1 - Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during melanoma tumorigenesis
AU - Shabaneh, Tamer B.
AU - Molodtsov, Aleksey K.
AU - Steinberg, Shannon M.
AU - Zhang, Peisheng
AU - Torres, Gretel M.
AU - Mohamed, Gadisti A.
AU - Boni, Andrea
AU - Curiel, Tyler J.
AU - Angeles, Christina V.
AU - Turk, Mary Jo
N1 - Funding Information:
The authors thank W. Green, R. Noelle, Y. Huang, and K. Hvorecny for helpful discussions, technical guidance, and providing reagents. We thank M. Bosenberg, N. Restifo, R. Noelle, and P. Antony for providing mice. PLX4720 was provided by Plexxikon Inc. under a Materials Transfer Agreement. This work was supported by NIH R21CA209375-01 (NCI), NIH R01CA120777-06 (NCI), NIH R01 CA225028, the generous philanthropy of the Knights of the York Cross of Honour, and a grant from The Melanoma Research Alliance, to M.J. Turk. This work was also supported by NIH R01CA205965 to T.J. Curiel. C.V. Angeles was supported by NIH KL2TR991088. T.B. Shabaneh was supported by NIH T32-AI0073634. Some analyses were carried out in DartLab, a shared resource supported (http://dx.doi.org/10.13039/100000002) by NIH P30CA023108-36 and NIH P30GM103415-14.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-18-0365
DO - 10.1158/0008-5472.CAN-18-0365
M3 - Article
C2 - 30026331
AN - SCOPUS:85052693904
VL - 78
SP - 5038
EP - 5049
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 17
ER -