Temporal optimization of CD25-biased IL-2 agonists and immune checkpoint blockade leads to synergistic anticancer activity despite robust regulatory T cell expansion

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F25%3A00638382" target="_blank" >RIV/61388971:_____/25:00638382 - isvavai.cz</a>

Result on the web

<a href="https://jitc.bmj.com/content/13/8/e010465" target="_blank" >https://jitc.bmj.com/content/13/8/e010465</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/jitc-2024-010465" target="_blank" >10.1136/jitc-2024-010465</a>

Result language

angličtina

Original language name

Temporal optimization of CD25-biased IL-2 agonists and immune checkpoint blockade leads to synergistic anticancer activity despite robust regulatory T cell expansion

Original language description

Background Interleukin-2 (IL-2) immunotherapy can induce durable tumor remissions, but its clinical performance has been limited by significant drawbacks such as short serum half-life and high toxicity. Administration of IL-2 in complex with certain anti-IL-2 antibodies (IL-2cx) enhances circulation half-life while also selectivity directing the cytokine to particular immune cell subsets. In particular, IL-2cx has been developed that targets either cells expressing the CD25-containing high-affinity IL-2 receptor (ie, CD25-biased IL-2cx) or cells expressing the CD25-lacking intermediate-affinity IL-2 receptor (ie, CD25-blocking IL-2cx). Since regulatory T (Treg) cells primarily express the high-affinity IL-2 receptor whereas na & iuml, ve effector T and natural killer cells mainly express the low-affinity IL-2 receptor, CD25-blocking IL-2cx have traditionally been considered as potential cancer therapeutics, particularly in combination with immune checkpoint inhibitors (ICIs).Methods Stimulation of antigen-primed T cells by IL-2cx in the absence or presence of ICIs was evaluated through adoptive transfer of primed ovalbumin-specific T cells and analysis of expansion. Effects of IL-2cx on Treg cell-mediated inhibition of CD8+ T cells were assessed by flow cytometry and thymidine incorporation. Tumor-bearing mice received combination treatments comprizing IL-2cx and ICIs, where complexes were delivered either before or after ICIs. Tumor growth and mouse survival were monitored, and immune cell phenotyping was performed. Toxicity was determined by tracking body weight, temperature, and lung edema. Substitution of IL-2cx with single-agent cytokine/antibody fusion proteins (immunocytokines, ICs) was also explored.Results We showed that CD25-biased IL-2cx and ICs synergize with ICIs to completely eradicate large, established tumors despite robust Treg cell expansion. Importantly, we found that timing is crucial, as administration of IL-2cx after (but not before) ICIs led to profound antitumor effects. Mechanistically, CD25-biased IL-2cx selectively stimulated expansion and effector functions of tumor-specific CD8+ T cells in a CD25-dependent manner, overcoming Treg cell-mediated suppression. Moreover, CD25-biased IL-2cx showed much lower toxicity than CD25-blocking IL-2cx, enabling a larger therapeutic window. Furthermore, we demonstrated that administration of a human IL-2-based IC significantly enhanced the antitumor activity of ICIs, establishing the translational relevance of our work.Conclusions Our findings support the temporally optimized use of CD25-biased IL-2-based therapeutics in combination with ICIs for cancer immunotherapy.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30102 - Immunology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal for ImmunoTherapy of Cancer

ISSN

2051-1426

e-ISSN

2051-1426

Volume of the periodical

13

Issue of the periodical within the volume

8

Country of publishing house

GB - UNITED KINGDOM

Number of pages

21

Pages from-to

e010465

UT code for WoS article

001552596200001

EID of the result in the Scopus database

2-s2.0-105013062718