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

Sep 4, 2024Journal for immunotherapy of cancer

Targeting IL-33 changes the tumor environment and may boost the response to anti-PD-L1 cancer immunotherapy

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Abstract

Blocking with a specialized fusion protein enhanced the antitumor efficacy of the PD-L1 antibody.

After treatment with anti-PD-L1, levels of tumor-infiltrating ST2 regulatory T cells increased.
Using the sST2-Fc fusion protein improved the effectiveness of the PD-L1 antibody by boosting T cell responses in tumor models.
The bifunctional fusion protein anti-PD-L1-sST2 showed greater antitumor activity than traditional combination therapy.
This enhanced activity was linked to a reduction in immunosuppressive factors, like regulatory T cells and exhausted CD8 T cells.
There was an increase in cytotoxic T lymphocyte cells within the tumors, contributing to improved antitumor immunity.

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BACKGROUND: The 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 /ST2 signal fulfills critical functions. However, whether IL-33 limits the therapeutic efficacy of anti-PD-L1 remains uncertain.

METHODS: Molecular 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.

RESULTS: After anti-PD-L1 administration, tumor-infiltrating ST2regulatory T cells () 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 CD8T cells while increasing tumor-infiltrating cytotoxic T lymphocyte cells. + +

CONCLUSIONS: In 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.

Key numbers

39 days

Median Survival Increase

Survival of mice treated with anti-PD-L1 monotherapy in the metastatic CT26 model.

11.5 mg/kg

Tumor Weight Reduction

Dosage of bifunctional fusion proteins in murine LLC models.

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

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