Intratumoral IL-1R1 Expression Delineates a Distinctive Molecular Subset with Therapeutic Resistance in Patients with Gastric Cancer

Background: With the essential role of interleukin-1 signaling in cancer-related inflammation, IL-1R1, the main receptor for both IL-1α and IL-1β, demonstrated therapeutic potential in several types of cancer, which has been put into clinical trials. However, the expression profile and critical role of IL-1R1 in gastric cancer (GC) remain obscure. This study aimed to investigate the prognostic significance of IL-1R1 expression and its predictive value for chemotherapy and immunotherapy in GC.

Methods: The study enrolled three cohorts, consisting of 409 tumor microarray specimens of GC patients from Zhongshan Hospital, 341 transcriptional data from , and 45 transcriptional data from patients treated with pembrolizumab. IL-1R1 mRNA expression was directly acquired from public datasets, and we also detected IL-1R1 protein expression on tumor microarray by immunohistochemistry. Finally, the associations of IL-1R1 expression with clinical outcomes, immune contexture, and genomic features were analyzed.

Results: High IL-1R1 expression predicted poor prognosis and inferior responsiveness to both 5-fluorouracil-based adjuvant chemotherapy (ACT) and immune checkpoint blockade (ICB). IL-1R1 fostered an immunosuppressive microenvironment characterized by upregulated M2 macrophages and exhausted CD8 T cells infiltration. Moreover, the expression of IL-1R1 was intrinsically linked to genomic alterations associated with targeted therapies in GC.

Conclusions: IL-1R1 served as an independent prognosticator and predictive biomarker for ACT and ICB in GC. Furthermore, IL-1R1 antagonists could be a novel agent alone or combined with current therapeutic strategies in GC.