Figure 3 from IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy

https://doi.org/10.1158/2767-9764.26538475

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posted on 2024-08-12, 09:20 authored by Charlotte J. Imianowski, Paula Kuo, Sarah K. Whiteside, Teresa von Linde, Alexander J. Wesolowski, Alberto G. Conti, Alexander C. Evans, Tarrion Baird, Benjamin I. Morris, Nicole E. Fletcher, Jie Yang, Edmund Poon, Matthew A. Lakins, Masahiro Yamamoto, Neil Brewis, Michelle Morrow, Rahul Roychoudhuri

OX40/CD137 dual agonism results in decreased CD25 expression and IL2 responsiveness of Tregs. A, Representative histograms and replicate measurements showing CD25 expression on CD4+ Tregs from the spleen (left) and tumor-draining lymph node (right). B, Schema showing setup of ex vivo IL2 assay (left), replicate measurements of Foxp3-GFP expression (center), and Treg count (right) after 4 days in culture with the indicated concentrations of IL2. C, Schema representing treatment schedule of tamoxifen, FS120m, and rIL2/anti-IL2 mAb complex. D, Representative plots (left) and replicate measurements (right) of the percentage of RFP+ SP exTregs (GFP−) out of total RFP+ cells in the tumors and spleens of reporter mice treated according to C. Data were analyzed by unpaired Student t test (A), unpaired Student t test with Bonferroni–Dunn correction for multiple comparisons (B), and one-way ANOVA with Tukey correction for multiple comparisons (D). Bars and error are mean and SEM. *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.0001; ****, P ≤ 0.0001. Ctrl, control; dLN, tumor-draining lymph node.

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DOI - Is supplement to IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy

ARTICLE ABSTRACT

Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs to contribute to antitumor immunity. OX40 and CD137 are expressed highly on Tregs, activated and memory T cells, and NK cells. In this study, using a novel bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonism induces potent antitumor immunity partially dependent upon IFNγ production by functionally reprogrammed Tregs. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Tregs into both fragile Foxp3+ IFNγ+ Tregs with decreased suppressive function and lineage-instable Foxp3− IFNγ+ ex-Tregs. Treg fragility is partially driven by IFNγ signaling, whereas Treg instability is associated with reduced IL2 responsiveness upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Tregs and their progeny partially reverses the antitumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Tregs into IFNγ-producing cells contributes to the anti-tumor efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting costimulatory receptors highly expressed by Tregs potentiate antitumor immunity in mouse models. The bispecific antibody FS120, an immunotherapy currently being tested in the clinic, partially functions by inducing anti-tumor activity of Tregs, which results in tumor rejection.

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Keywords

Immunology Tumor immunology animal models Regulatory T cells Immune responses to cancer Immunotherapy Agonist antibodies

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