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

Sep 22, 2026

Uploaded by Pentious

Cervical cancer shows limited, often short-lived benefit from programmed cell death protein 1 blockade despite viral etiology and immunogenic features. This study integrates spatial proteomics with bulk transcriptomic profiling to map the immune microenvironment in 65 resected tumors, assessing immune subset markers and clinically actionable checkpoint molecules by immunohistochemistry. Infiltration is largely stromal, with CD8+ and CD4+ T cells dominant, and distinct niche-enriched checkpoint expression. CD155 is consistently linked to poor survival and chemotherapy resistance across niches and cohorts, and emerges as the strongest functional therapeutic target for epithelial-directed precision immunotherapy beyond PD-1.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

ABSTRACT

Background

Methods

Results

Conclusion

WHAT IS ALREADY KNOWN ON THIS TOPIC

WHAT THIS STUDY ADDS

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Open access Original research CD155 links tumor immunotype to epithelial-directed precision therapy beyond checkpoint inhibition in cervical cancer Yannick Verhoeven ,1,2 Delphine Quatannens,1 Sanne van der Heijden,1 Jari Claes,3 Julie de Beukelaar,1 Hilde Lambrechts,1 Christophe Hermans,1 Glenn Broeckx,1,4 Herwig Van Dijck,5 Ali Ramadhan,5 Karen Zwaenepoel,1,5 Hans Stoop,5 Steven Van Laere,1 Jan Hauspy,6 Christel Faes,3 Léon C van Kempen,1,5 Xuan Bich Trinh,1,2,7 Filip Lardon,1 Senada Koljenovic,1,5 Peter André van Dam,1,2,7 Jorrit De Waele1 To cite: Verhoeven Y, Quatannens D, van der Heijden S, et al. CD155 links tumor immunotype to epithelialdirected precision therapy beyond checkpoint inhibition in cervical cancer. Journal for ImmunoTherapy of Cancer 2026;14:e014834 . doi:10 . 1136/ jitc-2026-014834 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2026-014834](jitc-2026-014834)) . Accepted 05 May 2026 © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. For numbered affiliations see end of article. Correspondence to Dr Jorrit De Waele; [jorrit.dewaele@uantwerp.be](jorrit.dewaele@uantwerp.be) ABSTRACT Background Despite its viral etiology and immunogenic features, cervical cancer shows limited and often shortlived 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 crossvalidated in The Cancer Genome Atlas cohort, and tumorkilling 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 | WHAT IS ALREADY KNOWN ON THIS TOPIC | | --- | | ⇒ Cervical cancer is considered immunogenic due to its viral etiology, high mutational burden, and dense immune infiltration; however, responses to current immunotherapy remain limited. Programmed cell death protein 1 (PD-1) targeting therapy is the only approved strategy in this setting, yet its clinical efficacy is modest and alternative immunoregulatory pathways remain underexplored.
WHAT THIS STUDY ADDS | | ⇒ This study delivers an integrative spatial and transcri

FAQs

Why is PD-1 blockade insufficient for cervical cancer?

Cervical cancer has immunogenic features due to viral etiology and immune infiltration, yet responses to PD-1 blockade are limited and often short-lived. This motivates identifying alternative or complementary immunotherapeutic targets.

What immune niches and cell subsets dominate in the tumors studied?

Immune infiltration is predominantly localized to tumor stroma, with CD8+ and CD4+ T cells as dominant subsets. Within tumor epithelium, CD8+ T cells and CD68+ macrophages are most abundant.

Which checkpoint molecule is highlighted as the key prognostic and therapeutic target?

CD155 stands out as the only checkpoint consistently linked with poor survival across niches and cohorts. It is also associated with chemotherapy resistance and shows the strongest functional therapeutic potential.

Sep 22, 2026

Uploaded by Pentious