Cytotoxic T cells play a central role in tumor immunity based on their ability to target tumor cells with a high degree of specificity. Checkpoint blockers that target the inhibitory CTLA-4 and PD-1 receptors on T cells have made a major impact on the treatment of melanoma and other human cancers. However, primary and secondary resistance to checkpoint blockade remain major clinical problems, and most melanoma patients still fail to benefit from these therapeutic agents. The goal of this project is to define the transcriptional and epigenetic mechanisms that render melanomas resistant to T cell-mediated immunity. We recently performed a genome-scale screen and discovered a large number of genes (n=128) that mediate resistance by melanoma cells to cytotoxic T cells. Of particular interest are three major transcriptional and epigenetic regulators, the PBAF form of the SWI/SNF complex as well as the SOX4 and NF-kB p65 transcription factors.
Aim 1 will focus on the role of PBAF complex in resistance to immunotherapy. The PBAF complex is relevant in human melanoma because the ARID2 gene is frequently mutated. Preliminary data demonstrate that inactivation of the genes encoding the three unique subunits of the PBAF complex (Pbrm1, Arid2 and Brd7) sensitizes murine melanoma cells to cytotoxic T cells. We will investigate the impact of the PBAF complex on the tumor microenvironment in human melanoma as well as murine and zebrafish models of melanoma. Mechanistic studies will focus on the epigenetic enzymes and transcription factors that cooperate with the PBAF complex to inhibit T cell-mediated tumor immunity.
Aim 2 will focus on the two major transcription factors ? NF-kB p65 and SOX4 ? that were discovered in the genetic screen. We will investigate whether the NF-kB and SOX4 transcription factors cooperate with the PBAF complex to confer resistance to cytotoxic T cells. The TNF??? NF-kB pathway was identified as the top resistance pathway in the screen, and we will investigate whether TNF? secreted by activated T cells renders neighboring tumor cells more resistant to T cell-mediated killing. The TNF? ? NF-kB pathway can induce either cell survival or cell death, and a number of gene products identified in the screen inhibit TNF? induced cell death, including the kinase TBK1. We will therefore investigate whether the outcome of TNF?-mediated signaling can be switched from tumor cell resistance to cell death using available TBK1 inhibitors. Expression of the transcription factor SOX4 is induced by TGF? following activation of latent TGF? by integrin ?V. Both genes encoding SOX4 (Sox4) and integrin ?V (Itgav) were identified as major resistance mechanisms in our genetic screen, and we will investigate whether this resistance pathway can be targeted with a mAb that inhibits integrin ?V mediated TGF? activation. This project will make a substantial contribution to this P01 through major collaborations with Drs. Fisher and Zon (melanoma models), Drs. Rodig, Hodi and Fisher (human melanoma) and Drs. Liu, Zon and Fisher (epigenetic mechanisms).

Public Health Relevance

This project focuses on the epigenetic and transcriptional regulators that confer melanoma cell resistance to cytotoxic T cells. We will investigate whether targeting of these epigenetic and transcriptional pathways sensitizes melanoma cells to immunotherapies in which T cells represent the major immune effector cell population. This question will be addressed using an integrated approach involving both relevant animal models and investigation of the immune microenvironment in human melanomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Massachusetts General Hospital
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Romano, Gabriele; Chen, Pei-Ling; Song, Ping et al. (2018) A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling. Cancer Discov 8:556-567
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Levy, Carmit; Golan, Tamar; Fisher, David E (2018) miRNA-211 stops the clock. Noncoding RNA Investig 2:
Eliades, Philip; Abraham, Brian J; Ji, Zhenyu et al. (2018) High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma. J Invest Dermatol 138:1582-1590
Nguyen, Nhu T; Fisher, David E (2018) MITF and UV responses in skin: From pigmentation to addiction. Pigment Cell Melanoma Res :
Kapp, Friedrich G; Perlin, Julie R; Hagedorn, Elliott J et al. (2018) Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature 558:445-448
Byrne, Elizabeth H; Fisher, David E (2017) Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 123:2143-2153
Lin, William M; Fisher, David E (2017) Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. Annu Rev Pathol 12:75-102
Kawakami, Akinori; Fisher, David E (2017) The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest 97:649-656
Reuben, Alexandre; Spencer, Christine N; Prieto, Peter A et al. (2017) Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. NPJ Genom Med 2:

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