Cross-talk between Schwann Cells and CD4+ T Cells Promotes Perineural Invasion in Colorectal Cancer

Vollständiger Abstract

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Abstract Perineural invasion (PNI) is a common pathologic feature associated with poor prognosis in colorectal cancer. A better understanding of the mechanisms underlying PNI formation could help identify potential strategies to inhibit tumor progression. In this study, we revealed an integral role of CD4+ T cells in the development and progression of PNI in colorectal cancer. Single-cell RNA sequencing, spatial transcriptomics, and multiplex IHC profiling uncovered a distinct HSPA6+ CD4+ T-cell subset expressing T stress (Tstr) cell markers in colorectal cancer PNI tissues. Schwann cells (SC) colocalized with the HSPA6+ CD4+ Tstr cells in PNI, and functional studies showed that SCs promoted Tstr cell differentiation, whereas Tstr cells enhanced SC migration. Interaction between SCs and CD4+ T cells activated the mitogen-activated protein kinase (MAPK) pathway in SCs and the JAK–STAT pathway in Tstr cells, and inhibition of MAPK and STAT signaling suppressed nerve invasion of colorectal cancer cells in vivo. Moreover, SCs in contact with tumor cells possessed the ability to recruit CD4+ T cells; tumor-derived TNFα stimulated SCs to secrete CCL4, thereby recruiting CD4+ T cells toward SCs. The anti-TNFα mAb infliximab reversed the proinvasive and promigratory effects of SCs on colorectal cancer 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 colorectal cancer 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. Significance: A CD4+ T cell subtype forms a feedback loop with Schwann cells that promotes perineural invasion in colorectal cancer and can be targeted to suppress tumor progression and enhance PD-1 blockade efficacy.