IL33-ST2 axis is a predictive biomarker for anti-PD1 therapeutic efficacy in advanced gastric cancer

We previously demonstrated that interleukin-33 (IL33) plays a key role in treatment resistance through tumor polyploidization and the consequent immune dysfunction by recruiting and expanding various immunosuppressive cells that express its receptor ST2, and that anti-IL33 blockade therapy induces potent anti-tumor effect in mouse tumor models resistant to anti-PD1 therapy. These suggest that IL33 and ST2 are potentially promising targets that could contribute to anti-PD1/PDL1 therapy. Recently, an increasing number of clinical studies have shown a significant correlation between IL33 expression in tumor tissues and poor prognosis in patients with gastric cancer (GC). However, the clinical significance of targeting the IL33-ST2 axis in anti-PD1/PDL1 therapy for GC remains unclear. Tumor tissues and peripheral blood were collected from patients with advanced GC before and after nivolumab monotherapy in the WJOG10417GTR study. Gene expression of il33 in tumor tissues, IL33 in plasma, and ST2+ cell subsets in four cell populations (IL17RB+GATA3+ ILC2s, CD117+FceRIa+ mast cells, CD11b+HLA-DR−PDL1+ MDSCs, and CD3+CD4+FOXP3+ Tregs) in peripheral blood cells were analyzed by RNA-sequencing, IHC, ELISA, or flow cytometry, and the relationship between their levels and patient prognosis was statistically analyzed. The levels of tumor il33 gene expression and peripheral IL33 and ST2+ cells were higher in patients who showed progressive disease (PD) than in non-PD patients. High levels of tumor il33 gene expression at post-treatment, and high levels of peripheral ST2+ cells at both pre- and post-treatment were significantly associated with shorter progression-free survival and overall survival. Patients with low post-treatment levels of both tumor il33 and peripheral ST2+ cells, especially the mast cell subset, had long-term survival without PD, indicating durable responders. These data suggest high IL33/ST2 levels are significant poor prognostic factors for nivolumab therapy for advanced GC. The IL33/ST2 axis may be useful as a biomarker for predicting and pre-selecting possible responders/nonresponders to anti-PD1/PDL1 therapy for GC, and hopefully as a druggable target for developing new drugs for treating GC. The IL33/ST2-targeting strategy will contribute to improving clinical outcomes in the treatment of GC.