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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Journal for ImmunoTherapy of Cancer

ISSN

2051-1426

e-ISSN

2051-1426

Svazek periodika

13

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

21

Strana od-do

e010465

Kód UT WoS článku

001552596200001

EID výsledku v databázi Scopus

2-s2.0-105013062718