The Role of Schwann Cells in the Progression of Melanoma

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.

Grant Number: 5R01CA266529-04
NIH Institute/Center: NIH
Principal Investigator: Yuri Bunimovich