SELP+ TEC:CD8+ T cell crosstalk associates with improved radiotherapy efficacy in cervical cancer

Abstract

P-selectin (SELP) expression in tumor cells has been implicated in promoting tumor progression and treatment resistance across various cancers. However, our prior study identified SELP expression in a specific subpopulation of endothelial cells within cervical cancer (CC) and potentially linked to anti-cancer immune response. The precise mechanisms by which SELP influences anti-cancer immunity and its involvement in radiotherapy response in CC, however, remain elusive. To address these gaps, this study analyzed tumor tissue samples from 205 CC patients undergoing radiotherapy, scRNA-seq data from 42,159 cells of eight patients, and bulk RNA-sequencing data from 187 radiotherapy-treated patients. The results revealed that elevated SELP expression in tumor endothelial cells (TECs) was significantly correlated with improved survival outcomes in patients treated with radiotherapy. The SELP^high group exhibited a prominent enrichment of immune-related pathways, coupled with a diminished enrichment in epithelial cell proliferation and angiogenesis pathways. Notably, this group demonstrated increased infiltration of CD8⁺ T cells and enhanced expression of chemokine receptors, including ACKR1. Furthermore, our data suggest that SELP⁺ TECs engage in crosstalk with CD8⁺ T cells via the ACKR1-CCL5 axis, which is associated with improved radiotherapy efficacy. In conclusion, these findings underscore the pivotal role of SELP⁺ TEC:CD8⁺ T cell interactions through the ACKR1-CCL5 pathway in enhancing radiotherapy response in CC. Targeting this crosstalk may offer novel therapeutic strategies to mitigate treatment resistance and improve patient survival.

Fig. 1

Association of SELP⁺ TEC with enhanced radiotherapy efficacy and immune activation in patients with CC. A Clinical characteristics of 205 patients with CC. B Representative immunohistochemical images of SELP expression in TECs. C Kaplan–Meier survival curves showing local recurrence-free survival in CC patients stratified by SELP expression levels. D Multivariate Cox proportional hazards analysis assessing the relationship between clinical characteristics and local recurrence-free survival in CC patients. E Kaplan–Meier survival curve demonstrating PFS of CC patients treated with radiotherapy in the SELP^high and SELP^low groups (with optimal cutoff value derived from the TCGA dataset). P-values from the two-sided log-rank test are shown. F Volcano plot illustrating differentially expressed genes between the SELP^high and SELP^low groups, with the most significant genes highlighted. G GO terms enriched in the SELP^high group. H Box plots comparing gene set scores between the SELP^high and SELP^low groups. I Violin plots displaying the expression levels of atypical chemokine receptor genes in CC patients

Fig. 2

Correlation of SELP⁺ TEC:CD8⁺ T cell crosstalk with improved radiotherapy outcomes and enhanced immune responses in patients with CC. A UMAP plots showing the expression of SELP in 2,569 TECs, color-coded by SELP expression levels, stratified by the median SELP expression value. B Representative images of immunofluorescence staining for CD62P in TECs within tumor tissue. C Volcano plot depicting differentially expressed genes between SELP⁺ TECs and SELP^– TECs. D GO terms enriched in SELP⁺ TECs and SELP^– TECs. E Heatmap illustrating intercellular communication between TECs and NK/T cell subclusters via the CCL signaling pathway. Color intensity reflects the probability of communication. F Bubble plots showing specific ligand–receptor interactions from the CCL signaling pathway involved in TEC–NK/T cell crosstalk. Bubble size indicates P-values, and color intensity reflects the interaction probability. G Kaplan–Meier survival curve demonstrating PFS in CC patients treated with radiotherapy, stratified by CCL signaling pathway score, CCL5 expression, and ACKR1 expression in the TCGA dataset. H Immunofluorescence staining revealing the interaction between CD62P⁺ endothelial cells (green for CD62P) and CD8⁺ T cells (red) via the ACKR1-CCL5 axis. CCL5 is shown in purple, ACKR1 (CD234) in orange, and nuclei in blue (DAPI staining). The merged image illustrates the colocalization of these markers within the tissue (scale bar = 40 μm). TECs, tumor endothelial cells; OS, overall survival; PFS, progression-free survival; CC, cervical cancer; UMAP, uniform manifold approximation and projection