Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy

• Published in: Journal for immunotherapy of cancer 2024-09, Vol.12 (9), p.e009236
• Main Authors: Nan, Yanyang, Bai, Yu, Hu, Xiaozhi, Zhou, Kaicheng, Wu, Tao, Zhu, An, Li, Mengyang, Dou, Zihan, Cao, Zhonglian, Zhang, Xumeng, Xu, Shuwen, Zhang, Yuanzhen, Lin, Jun, Zeng, Xian, Fan, Jiajun, Zhang, Xuyao, Wang, Xuebin, Ju, Dianwen
• Format: Article
• Language: English
• Subjects: Animals; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Cancer therapies; Cell death; Cell Line, Tumor; Clinical/Translational Cancer Immunotherapy; Combination therapy; Cytokines; Fibroblasts; Gene expression; Genomics; Humans; Immune Checkpoint Inhibitor; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune modulatory; Immunotherapy; Immunotherapy - methods; Interleukin-1 Receptor-Like 1 Protein - metabolism; Interleukin-33; Metastasis; Mice; Mice, Inbred C57BL; Original Research; Proteins; T regulatory cell - Treg; Tumor Microenvironment; Tumor microenvironment - TME; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2024-009236

BackgroundThe main challenge against patients with cancer to derive benefits from immune checkpoint inhibitors targeting PD-1/PD-L1 appears to be the immunosuppressive tumor microenvironment (TME), in which IL-33/ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain.MethodsMolecular mechanisms of IL-33/ST2 signal on anti-PD-L1 treatment lewis lung carcinoma tumor model were assessed by RNA-seq, ELISA, WB and immunofluorescence (IF). A sST2-Fc fusion protein was constructed for targeting IL-33 and combined with anti-PD-L1 antibody for immunotherapy in colon and lung tumor models. On this basis, bifunctional fusion proteins were generated for PD-L1-targeted blocking of IL-33 in tumors. The underlying mechanisms of dual targeting of IL-33 and PD-L1 revealed by RNA-seq, scRNA-seq, FACS, IF and WB.ResultsAfter anti-PD-L1 administration, tumor-infiltrating ST2+ regulatory T cells (Tregs) were elevated. Blocking IL-33/ST2 signal with sST2-Fc fusion protein potentiated antitumor efficacy of PD-L1 antibody by enhancing T cell responses in tumor models. Bifunctional fusion protein anti-PD-L1-sST2 exhibited enhanced antitumor efficacy compared with combination therapy, not only inhibited tumor progression and extended the survival, but also provided long-term protective antitumor immunity. Mechanistically, the superior antitumor activity of targeting IL-33 and PD-L1 originated from reducing immunosuppressive factors, such as Tregs and exhausted CD8+ T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells.ConclusionsIn this study, we demonstrated that IL-33/ST2 was involved in the immunosuppression mechanism of PD-L1 antibody therapy, and blockade by sST2-Fc or anti-PD-L1-sST2 could remodel the inflammatory TME and induce potent antitumor effect, highlighting the potential therapeutic strategies for the tumor treatment by simultaneously targeting IL-33 and PD-L1.