CD155 links tumor immunotype to epithelial-directed precision therapy beyond checkpoint inhibition in cervical cancer

Abstract

Background Despite its viral etiology and immunogenic features, cervical cancer shows limited and often short-lived benefit from programmed cell death protein 1 blockade, currently the only approved immunotherapy for this disease. This limitation highlights the need for a deeper understanding of its immune microenvironment to uncover alternative or complementary immunotherapeutic targets that may improve outcomes. Methods We integrated spatial proteomic and bulk transcriptomic profiling of the cervical cancer immune landscape. Immune subset markers (CD8, CD4, CD68, FoxP3, NKp46) and clinically actionable immune checkpoint molecules (HLA-E, CD47, CD73, CD276, CD155, Gal-9, PD-L1, CD70, LAG-3) were assessed by immunohistochemistry in 65 resected tumors, spatially resolved across tumor stroma and tumor epithelium niches. Expression patterns and correlations with clinicopathological variables, immunotypes, and survival were systematically analyzed. Key findings were cross-validated in The Cancer Genome Atlas cohort, and tumor-killing assays were conducted to evaluate the therapeutic potential of identified checkpoint axes. Results Immune infiltration was predominantly localized to the tumor stroma, with CD8(+) and CD4(+) T cells as dominant subsets. Within the tumor epithelium, CD8(+) T cells and CD68(+) macrophages were most abundant. Among checkpoints, HLA-E and CD47 showed the highest and most widespread expression, whereas CD276 and CD155 were enriched in the tumor epithelium, and CD73 and CD70 in the tumor stroma. Squamous cell carcinoma showed a stronger immunologic profile than adenocarcinoma. Immunotype stratification revealed distinct expression profiles and prognostic patterns. Elevated niche-defined expression of CD8, CD4, CD4-FoxP3, and NKp46 associated with improved survival. CD155 emerged as the only checkpoint consistently linked with poor survival across niches and cohorts, and associated with chemotherapy resistance. Notably, CD155 was the most promising functional target and was highly and selectively enriched in the tumor epithelium across all immunotypes, including immune-desert tumors where other immune markers were scarce. Conclusion This study reveals a complex, niche-specific and immunotype-specific immunoregulatory architecture in cervical cancer that extends well beyond programmed death-ligand 1. CD155 stands out as a compelling and underused therapeutic target, supporting a paradigm shift in targeting the T cell immunoreceptor with Ig and ITIM domains (TIGIT) axis. Its functional impact and selective enrichment in the tumor epithelium positions CD155 as a promising therapeutic target for both checkpoint inhibition and epithelial-directed approaches in cervical cancer.