Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis

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 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. .

Contribution of regulatory T cells to cancer: A review

“…Regulatory T cells (Tregs) are identified as immunosuppressive subset of CD4 + T cells (D. Wang, Quiros, et al, ) that represent about 4–5% of the whole CD4 + T‐cell population in normal conditions (Mougiakakos et al, ), and they work for preserving immune tolerance and suppressing autoimmune diseases (D. Wang, Quiros, et al, ). Tregs are identified as the prevailing T‐cell responders to the early tumors outpacing cytotoxic T lymphocytes (CTLs) during early tumor growth (Shabaneh et al, ). To maintain immune system in homeostasis, there is a tight regulation over Treg development (Y. Liu, Zhang, et al, ).…”

The emerging role of regulatory T cells following lung transplantation

“…By using the NOD mouse model, Tang et al were able to show that, in vitro, expanded Tregs are capable of inhibiting autoimmune diabetes after adoptive transfer. 36 In human colorectal cancer, accumulation of Tregs within tumors is associated with metastasis. A phase I trial in humans with type I diabetes showed that a substantial proportion of adoptively transferred Tregs can survive long term and may maintain pancreatic endocrine function, providing a platform for the development of future clinical trials.…”

“…In a mouse model of melanoma, for example, Tregs infiltrate the skin after tumor induction and lead to an increase in the Treg:CD8 + T cell ratios. 36 In human colorectal cancer, accumulation of Tregs within tumors is associated with metastasis. 37 Similarly, in the setting of some infections such as lymphocytic choriomeningitis virus, antigenspecific Tregs increase in the peripheral blood.…”

“…39 Such antigen specificity is important in cancer as well, where adoptive transfer of Tregs specific for a melanocyte antigen results in their accumulation within the tumor's draining lymph nodes. 36 One mechanism to explain a requirement for antigen specificity is that Tregs reduce the antigenpresenting capacity of dendritic cells and physically inhibit the contact of T cells and dendritic cells. 40 Once inflammation is suppressed, these antigen-specific Tregs lie dormant but retain the capacity to mount an even greater immune response should the host be challenged again.…”

CD3+CD56+ natural killer T cell infiltration is increased in cervical cancer and negatively correlated with tumour progression

“…Although tumour tissues are infiltrated by a large number of immune cells, it is still difficult to prevent the invasion and metastasis of tumour cells, suggesting that tumour cells can escape surveillance and killing by immune cells [10,11]. It is also discovered that tumour cells can induce differentiation of immune cells [12], for example, TAM2 macrophages and Tregs [13,14]. Therefore, further understanding of the interaction between tumour cells and immune cells provides us with the possibility of screening new targets.…”