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.

KEYWORDS:

• Cancer
• melanoma
• neuroimmunology
• Schwann cell
• tumor microenvironment

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The RNA sequencing data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE208150 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE208150).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2192098

Significance

Schwann cells have been implicated in cancer progression, but their functions in the tumor microenvironment are unclear. We demonstrate that Schwann cells in the skin adjacent to melanomas are reprogrammed to repair-like Schwann cells which impede anti-tumor T-cell activity by upregulating the production of immunosuppressive eicosanoids.

Additional information

Funding

This project was supported by the Research Scholar Grant, RSG-19-088-01-CSM, from the American Cancer Society (YLB), by awards R01CA266529 (YLB) and R01CA165065 (VEK), and by the Hillman Fellows for Innovative Cancer Research Program funded by the Henry L. Hillman Foundation (YLB). This project utilized the University of Pittsburgh Imaging Core that is supported in part by award P01HL114453, and the Hillman Cancer Genomics Facility and Bioinformatics Services, supported in part by award P30CA047904.