Pan-cancer analysis of STAT6 expression and its relationship with tumor microenvironment characteristics and survival.

Abstract

2585 Background: Co-targetable immune pathways influence cancer outcomes and responses to immune checkpoint inhibitors (ICIs). We examined the transcriptomic expression and clinical significance of signal transducer and activator of transcription-6 (STAT6), an immune-modulatory signaling factor activated by IL-4 and IL13 and involved in innate immunity in infection and cancer. Methods: Transcriptomic expression across 395 genes was measured in various solid tumors from 514 patients with advanced cancer, normalized to a reference population (n=735), and reported as percentiles (high defined as ≥75th percentile). We evaluated association between high STAT6 expression and transcriptomic expression of STAT6-related markers (IL4, IL13, TGFB1, IL10, CD8, CCL18, TNFRSF14 [HVEM], VISTA) and currently targetable immune checkpoints (PD-1, PD-L1, PD-L2, CTLA-4, LAG3). Genomic alterations were also assessed for the association with high STAT6 expression. Variables with P<0.2 in univariable analysis were included in the subsequent multivariable logistic regression model incorporating genomic, immunomic, and clinical factors. Clinical outcomes were evaluated using Kaplan–Meier method and Cox regression model. Results: High STAT6 expression was observed in 184 patients (35.8%); 2 (0.4%) had zero measurable expression. High STAT6 was associated with TMB <10 muts/Mb, high expression of LAG3, PD-L2, IL13, TNFRSF14 (HVEM), and VISTA (all immunosuppressive), and a diagnosis of colorectal cancer in multivariable analysis. Breast cancer was negatively associated with high STAT6. In univariable analysis, alterations in SMAD4, KRAS, and APC were significantly associated with high STAT6, though none remained significant in the multivariable model. In advanced cancer patients, high STAT6 was associated with shorter survival (N=489 with clinical data curated, Hazard ratio 1.44, 95% confidence interval 1.03–2.02, p=0.034). Among 217 ICI-treated patients, high STAT6 did not correlate with survival. Conclusions: High STAT6 expression associates with a biologically coherent tumor microenvironment characterized by factors mediating profound immune suppression. The STAT6-high phenotype is mechanistically linked to an exhausted immune landscape, evidenced by the co-expression of inhibitory checkpoints LAG3 and VISTA, and may be further driven by an IL13/STAT6 autocrine loop. Clinically, high STAT6 correlates with shorter survival in patients with advanced cancers. Prospective validation of this STAT6-driven signature is warranted to guide the development of precision therapy trials aimed at co-targeting this pathway to improve outcomes.