The Role of Schwann Cells in the Progression of Melanoma

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Project Summary Clinical and experimental evidence demonstrate that cancer progression depends on the interactions of malignant cells with other elements of the tumor microenvironment (TME). Functions of cancer-associated fibroblasts, endothelial cells, tumor-infiltrating immune cells and other stromal elements in regulating tumor growth and progression have been intensively investigated. Peripheral neurons are now also recognized as important constituents of the tumor milieu. The degree of tumor innervation is directly correlated with cancer progression and metastasis, and inversely correlated with patient survival. Several mechanisms responsible for nerve-mediated cancer progression have been proposed, including regulatory activity of neurotransmitters and neuropeptides on tumor-associated vasculature and immune infiltrate. Thus far, work in this area largely focused on the role of the autonomic nervous system in promoting cancer, with several reports also implicating the somatic afferent innervation. However, the role of the neuroglia of the peripheral nervous system in promoting cancer progression remains unclear. Specifically, excluding the process of perineural invasion, the extent to which Schwann cells (SCs), principal glia of the peripheral nervous system, modulate TME and facilitate cancer progression has not been investigated. We demonstrated that SCs are present in human melanoma tissue, and that they accelerate tumor growth and metastasis in several melanoma mouse models. We discovered that this effect is due to the activation of repair SCs, and their inhibition of tertiary lymphoid structure (TLS) formation and protective anti-tumor immune responses. However, the mechanism of SC immunomodulation in TME remains unknown. We hypothesize that melanoma-associated repair SCs promote immune tolerance to melanoma, and their targeting is a novel immunotherapy approach against cancer. To test our hypothesis, we will pursue two Specific Aims: 1) determine the mechanism of immunomodulation by repair SCs in melanoma, and 2) target repair SCs in melanoma as a novel approach to therapy. In Aim 1, we will examine how SCs promote immune tolerance of cancer and impede TLS formation in tumors, focusing on Slit2, MAG, and p75NTR signaling mechanisms. Transgenic immunocompetent autochthonous BrafCA melanoma and slow Wallerian degeneration WldS mouse models will be utilized. In Aim 2, we will test whether targeting melanoma-associated repair SCs to break immune tolerance synergizes with current anti-PD-1 and anti-CTLA4 therapies. The primary impact of the proposal will be mechanistic verification of SC-dependent maintenance of the immune tolerance – a major challenge in the current treatment of advanced malignancies. We expect that our results will validate a novel immunotherapy approach for melanoma based on targeting tumor-associated glia – an approach which will likely be applicable to other types of cancer.