Abstract A047: B7-H4 expression and CCR8+ Treg infiltration delineate an immune-cold molecular phenotype in ovarian cancer

Abstract Background: B7-H4 (VTCN1) is a nonclassical immune checkpoint implicated in tumor immune evasion. CCR8 marks tumor-resident regulatory T cells (Tregs) with potent suppressive activity. Their coexistence in ovarian cancer may define an immune-cold phenotype with therapeutic relevance. This study characterizes the relationship between VTCN1 expression and CCR8+ Treg infiltration using The Cancer Genome Atlas (TCGA) dataset. Methods: Transcriptomic (RNA-seq RSEM z-scores), somatic mutation, and copy-number data from the TCGA-OV PanCancer Atlas (n = 430) were analyzed via cBioPortal. High VTCN1 expression was defined as z ≥ 1.5. A CCR8-Treg signature was computed as the scaled mean of CCR8, FOXP3, IL2RA, CTLA4, and IKZF2. Associations between VTCN1 status and CCR8-Treg score, homologous recombination deficiency (HRD), tumor mutational burden (TMB), and driver mutations (TP53, BRCA1/2, PTEN, PIK3CA, ARID1A, NF1) were assessed using Wilcoxon and Fisher exact tests with false-discovery-rate correction. Overall survival (OS) was evaluated by Kaplan–Meier analysis. Analyses were performed in R 4.3. Generative artificial-intelligence tools (OpenAI GPT-5) were used under author supervision for data-processing scripts and text refinement, per AACR 2026 policy. Results: VTCN1 overexpression occurred in 31 % of tumors and was independent of HRD or BRCA status. VTCN1-high cases exhibited significantly higher CCR8-Treg scores (median +1.1 z-units; p 0.001) and increased FOXP3 and IL2RA expression, consistent with enrichment of CCR8+ Tregs. This association persisted after adjustment for tumor stage and TMB. Genomic VTCN1 alterations were rare ( 1 %), confirming transcriptional regulation. No significant differences were observed in TP53 mutations; however, VTCN1-high tumors showed a trend toward PI3K–AKT pathway alterations (PIK3CA, PTEN; FDR = 0.07). Integrative clustering revealed an “immune-silent” subgroup (∼25 % of samples) characterized by B7-H4 upregulation, high CCR8-Treg scores, low CD8 infiltration, and reduced IFNG-pathway activity. Exploratory survival analysis suggested worse OS in this subset (hazard ratio 1.6; 95 % CI 1.1–2.3; p = 0.03). Coexpression with MUC1 and TROP2 occurred in approximately 20 % of VTCN1-high cases, suggesting potential dual-targeting opportunities. Conclusions: B7-H4 overexpression defines an immune-suppressive phenotype in ovarian cancer enriched for CCR8+ Tregs and PI3K–AKT alterations, independent of HRD status. These data highlight the potential of combined B7-H4 and CCR8-directed immunotherapies in immune-cold ovarian tumors and underscore the utility of integrative TCGA analyses for rational target discovery. Disclosure on use of generative AI: This abstract includes text generated or refined with the assistance of a generative artificial-intelligence tool, under the direction and full review of the authors. Citation Format: Edwin MQ. BELLIDO, Valentina Boni, Jesus Fuentes, Juan Fusco, Ilaria Colombo. B7-H4 expression and CCR8+ Treg infiltration delineate an immune-cold molecular phenotype in ovarian cancer abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A047.