CDH17 expression and tumor microenvironment composition in gastric cancer.

4033 Background: Cadherin 17 (CDH17), commonly referred to as liver-intestine cadherin, is a calcium-dependent cell adhesion molecule, is overexpressed across multiple gastrointestinal epithelial malignancies and is implicated in tumorigenesis and aggressive tumor phenotypes through diverse signaling pathways. Preclinical studies have demonstrated the therapeutic potential of anti-CDH17 approaches across multiple therapeutic modalities. However, the relationship between CDH17 and cellular characteristics within the gastric cancer tumor microenvironment (TME) is yet to be sufficiently characterized. Methods: To systematically investigate the association between CDH17 expression and TME composition in gastric cancer, we conducted a comprehensive multi-cohort analysis of clinically annotated gastric cancer samples with RNA sequencing data. Within each cohort, CDH17 expression levels were quantified and dichotomized into high and low expression groups based on cohort-specific median transcripts per million (TPM) values. We applied the xCell immune deconvolution algorithm to estimate the relative immune and stromal cell populations enrichment across all samples. Results: In total, we studied 1,811 samples within ten datasets. CDH17 high-expressing gastric cancers demonstrated a distinctive TME signature characterized by selective cellular depletion rather than generalized immune suppression. Natural killer (NK) cell enrichment was identified in three cohorts; however, this pattern lacked pan-cohort consistency. Notably, CDH17 high expression was associated with significant depletion in multiple critical effector populations, including CD8+ cytotoxic T lymphocytes (CD8+ T-cells: 6/10 cohorts p < 0.05), myeloid dendritic cells and cancer-associated fibroblasts (8/10 cohorts, p < 0.05), and hematopoietic stem cells (5/10 cohorts, p < 0.05). In contrast, other immune and stromal cell populations demonstrated heterogeneous patterns of association with CDH17 expression, with no clear or uniform enrichment or depletion across cohorts. Conclusions: CDH17 high-expressing gastric cancers harbor an immunologically "cold" tumor microenvironment characterized by selective depletion of critical effector immune and stromal cell populations.