Melanoma-associated repair-like Schwann cells suppress anti-tumor T-cells via 12/15-LOX/COX2-associated eicosanoid production

Abstract

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses.

A novel induced pluripotent stem cell model of Schwann cell differentiation revealsNF2- related gene regulatory networks of the extracellular matrix

“…Growth factors and cell cycle inhibitors, such as LOX and CDKN2B, were also present in the blue module and conserved in cross-species analysis. LOX is a tumor suppressor gene, which when mutated in Schwann cells, can suppress T-cells in the melanoma tumor microenvironment [45]. CDKN2B is a cell cycle inhibitor that can induce proliferation when deleted or mutated in a multitude of cancer types [46][47][48].…”

Lipoxygenases at the Intersection of Infection and Carcinogenesis

“…In bladder cancer, p53 activates ALOX15B by inhibiting SLC7A11, leading to the induction of ferroptosis in bladder cancer cells [203]. In melanoma tumors, the blocking of ALOX5 or ALOX12-associated eicosanoid production reverses Schwann cell-dependent suppression of anti-tumor T cell activation [251] Current clinical trials targeting malignant glioma have shown promising therapeutic benefits from using herpes simplex virus thymidine kinase (HSV-TK) gene therapy [252]. However, when HSV-TK was combined with ALOX15 using adenoviral vectors in BT4C malignant glioma cells, there was no notable increase in tumor growth inhibition.…”