IL33-ST2 axis as a diagnostic and therapeutic biomarker in nivolumab therapy for advanced gastric cancer.
Authors: Kudo-Saito Chie , Boku Narikazu , Shoji Hirokazu , Imazeki Hiroshi , Nagashima Kengo , Tsugaru Kai , Takahashi Naoki , Kawakami Takeshi , Amanuma Yusuke , Wakatsuki Takeru , Okano Naohiro , Narita Yukiya , Yamamoto Yoshiyuki , Kizawa Rika , Aoki Kazunori , Muro Kei 
Published: June 2024

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Background: We previously identified IL33 as a determinant of treatment resistance of cancer using mouse tumor models and clinical samples. We showed that upon receiving treatment stress with immune checkpoint inhibitors, IL33+ tumor cells release IL33, which systemically expands immunoregulatory ST2+ cells (ILC2, mast cells [MCs], MDSCs, and Tregs) that facilitate tumor progression and metastasis directly and indirectly through induction of immune dysfunction, leading to refractory cancer. However, the clinical relevancy of targeting the IL33-ST2 axis in anti-PD1 therapy remains to be determined. Methods: We collected peripheral blood and biopsy tumor tissues from 96 patients with advanced gastric cancer before and after nivolumab monotherapy in the WJOG10417GTR study according to the protocol (No. 2017-473) approved by the IRB. Serum IL33 was measured by ELISA, peripheral blood cells were analyzed by flow cytometry for ST2+ cell populations, and tumor tissues were analyzed by RNA sequencing for il33 gene expression. Progression-free survival (PFS) and overall survival (OS) were compared between high/low groups divided by the cutoff value determined by visually assessing the continuous trend and change point of log hazard ratios obtained by applying penalized splines to each marker. Results: The high tumor il33 levels at post-treatment were significantly associated with worse prognosis as compared to the low levels (median PFS [mPFS] 54.5 vs 104 days, HR = 3.539, P = 0.002; median OS [mOS] 196 vs 418 days, HR = 2.659, P = 0.014), albeit serum IL33 levels showed no significant difference in PFS or OS. The high levels of ST2+ cells, including IL17RB+ ILC2s, CD117+FceRIa+ MCs, CD11b+HLA-DR-PDL1+ MDSCs, and CD3+CD4+CTLA4+FOXP3+ Tregs, at both timings were also significantly (P < 0.05) associated with worse prognosis as compared to the low levels. In combination of the tumor il33 expression levels and the ST2+ cell levels, particularly MCs at post-treatment, all of four patients with IL33-low/MC-low were responders who were alive until data cut-off (longer than 24 months), as compared with other groups with il33-low/MC-high (mPFS = 2.50 months, HR = 12.19, P = 0.020; and mOS = 8.85 months, N.A.), il33-high/MC-low (mPFS = 1.94 months, HR = 22.53, P = 0.011; and mOS = 8.59 months: N.A.), or il33-high/MC-high (mPFS = 1.68 months: HR = 31.47, P = 0.003; and mOS = 6.44 months: N.A.). Conclusions: These results suggest that the combinatory assessment of IL33 expression in tumors and ST2+ cells in peripheral blood, particularly MCs after treatment, is predictable of anti-PD1 responders with durable responses. Targeting the IL33-ST2 axis may be promising diagnostic and therapeutic strategies to improve the clinical outcome in the treatment of advanced gastric cancer. IL33 protein expression in tumors is now being assessed by immunostaining.