Crosstalk Between Schwann Cells and CD4+ T Cells Promotes Perineural Invasion in Colorectal Cancer

Perineural invasion (PNI) is a common pathological feature associated with poor prognosis of colorectal cancer (CRC). A better understanding of the mechanisms underlying PNI formation could help identify potential strategies to inhibit tumor progression. Here, we revealed an integral role of CD4+ T cells in the development and progression of PNI in CRC. Single-cell RNA sequencing, spatial transcriptomics, and multiplex immunohistochemistry profiling uncovered a distinct HSPA6+CD4+ T cell subset expressing T stress (Tstr) cell markers in CRC PNI tissues. Schwann cells (SCs) colocalized with the HSPA6+CD4+ Tstr cells in PNI, and functional studies showed that SCs promoted Tstr cell differentiation while Tstr cells enhanced SC migration. Interaction between SCs and CD4+ T cells activated the MAPK pathway in SCs and the JAK-STAT pathway in Tstr cells, and inhibition of MAPK and STAT signaling suppressed nerve invasion of CRC cells in vivo. Moreover, SCs in contact with tumor cells possessed the ability to recruit CD4+ T cells; tumor-derived TNF-α stimulated SCs to secrete CCL4, thereby recruiting CD4+ T cells toward SCs. The anti-TNF-α monoclonal antibody infliximab reversed the pro-invasive and pro-migratory effects of SCs on CRC cells and reduced intratumoral CD4+ Tstr cells, and the combination of infliximab with anti-PD-1 treatment produced a combinatorial tumor suppressive effect. Together, this study suggests that SCs near CRC tissues recruit CD4+ T cells and promote their conversion to CD4+ Tstr cells to establish an immunosuppressive microenvironment and simultaneously enhance the migration and tumor-promoting capabilities of SCs, thereby accelerating PNI development.