Mutual interaction between Schwann cells and CD4+T cells promotes the progression of perineural invasion in colorectal cancer [RNA-seq]

Background: Perineural invasion (PNI) is a common pathological feature associated with poor prognosis of colorectal cancer (CRC). However, the mechanisms underlying PNI formation and its relationship with CD4+T cells within the tumor immune microenvironment remain unclear. Aims: This study investigated the role of CD4+T cells in the development and progression of PNI in CRC by examining the interactions between Schwann cells (SCs), primary glial cells in peripheral nerves, and CD4+T cells. Methods: Single-cell RNA sequencing, spatial transcriptomics, and multiplex immunohistochemistry were used to profile the characteristics and spatial relationship between SCs and CD4+T cells in PNI CRC tissues. This study established an SCs-CD4⁺T-cells co-culture system and used flow cytometry, transcriptomic sequencing, proteomics, and ATAC-seq to investigate the mechanisms of their interaction. The key findings were validated in mouse models of sciatic nerve invasion and subcutaneous tumor formation. Finally, the origin of PNI was explored by co-culturing SCs with CRC cells. Results: The results revealed the presence of a distinct heat shock protein family A member 6 (HSPA6)+CD4+T cell subset—CD4+Tstr cells—in CRC PNI tissues. These cells are induced by SCs, further enhancing SCs' migration and tumor-promoting capabilities while contributing to an immunosuppressive microenvironment. Moreover, SCs in contact with tumor cells possess the ability to recruit CD4+T cells, potentially representing a key mechanism underlying PNI formation. Conclusion: This study suggests that SCs near CRC tissues recruit CD4+T cells, promote their conversion to CD4+Tstr cells, establish an immunosuppressive microenvironment, and simultaneously enhance SCs' migration and tumor-promoting capabilities, thereby accelerating PNI development.