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

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.

Resident memory T cells in the skin mediate durable immunity to melanoma.

Tissue-resident memory T (T) cells have been widely characterized in infectious disease settings; however, their role in mediating immunity to cancer remains unknown. We report that skin-resident memory T cell responses to melanoma are generated naturally as a result of autoimmune vitiligo. Melanoma antigen-specific T cells resided predominantly in melanocyte-depleted hair follicles and were maintained without recirculation or replenishment from the lymphoid compartment.

Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors.

Acquired resistance to BRAF inhibitors (BRAFi) in melanoma remains a common clinical obstacle, as is the case for any targeted drug therapy that can be developed given the plastic nature of cancers. Although there has been significant focus on the cancer cell-intrinsic properties of BRAFi resistance, the impact of BRAFi resistance on host immunity has not been explored. Here we provide preclinical evidence that resistance to BRAFi in an autochthonous mouse model of melanoma is associated with restoration of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, initially reduced by BRAFi treatment.

BRAF-inhibition and tumor immune suppression.

As BRAF-inhibitors become standard treatment for many metastatic melanoma patients, research has begun to elucidate their impact on the tumor immune landscape. Here, we highlight our recent studies demonstrating the ability of melanoma cell-intrinsic BRAF-inhibition to selectively reduce intratumoral immunosuppressive cell populations and enhance antitumor CD8 T-cell immunity.

BRAF inhibition alleviates immune suppression in murine autochthonous melanoma.

A growing body of evidence suggests that BRAF inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present study aimed to define the immunologic basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4(+)Foxp3(+) regulatory T cells (Treg) and CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8(+) effector T cells.

Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032.

The BRAF mutation, which approaches 50% in human melanomas, constitutively activates pERK and contributes to disease progression. The BRAF inhibitor, Vemurafenib (PLX4032), shows promising clinical responses, but resistance to PLX4032 usually develops within a year. Transgenic mouse models allow the study of BRaf melanoma , however models are necessary to better understand the molecular mechanism underlying disease progression and resistance.

Autoimmune vitiligo does not require the ongoing priming of naive CD8 T cells for disease progression or associated protection against melanoma.

Vitiligo is a CD8 T cell-mediated autoimmune disease that has been shown to promote the longevity of memory T cell responses to melanoma. However, mechanisms whereby melanocyte/melanoma Ag-specific T cell responses are perpetuated in the context of vitiligo are not well understood. These studies investigate the possible phenomenon of naive T cell priming in hosts with melanoma-initiated, self-perpetuating, autoimmune vitiligo.

Clonal immortalized human glial cell lines support varying levels of JC virus infection due to differences in cellular gene expression.

JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells).

Protective CD8 memory T cell responses to mouse melanoma are generated in the absence of CD4 T cell help.

Background: We have previously demonstrated that temporary depletion of CD4 T cells in mice with progressive B16 melanoma, followed by surgical tumor excision, induces protective memory CD8 T cell responses to melanoma/melanocyte antigens. We also showed that persistence of these CD8 T cells is supported, in an antigen-dependent fashion, by concurrent autoimmune melanocyte destruction. Herein we explore the requirement of CD4 T cell help in priming and maintaining this protective CD8 T cell response to melanoma.

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma.

A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8+ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4+ T cells and then subjected to surgical excision of large established B16 melanomas.