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 naïve 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.

• Klíčová slova
• Cytokine, Immune Checkpoint Inhibitor, Immunotherapy, T cell, T regulatory cell - Treg,
• MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů * farmakologie   terapeutické užití   MeSH
• interleukin-2 * agonisté   farmakologie   MeSH
• lidé MeSH
• myši MeSH
• receptor interleukinu-2 - alfa-podjednotka * metabolismus   agonisté   MeSH
• regulační T-lymfocyty * imunologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory kontrolních bodů * MeSH
• interleukin-2 * MeSH
• receptor interleukinu-2 - alfa-podjednotka * MeSH

T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

• Klíčová slova
• ABIN1, Antigen Receptor, Co-stimulation, T Cells, p38,
• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• aktivace lymfocytů imunologie   genetika   MeSH
• cytotoxické T-lymfocyty * imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu imunologie   genetika   metabolismus   MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• receptory OX40 metabolismus   genetika   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční * MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• NF-kappa B MeSH
• receptory antigenů T-buněk MeSH
• receptory OX40 MeSH
• Tnfrsf18 protein, mouse MeSH Prohlížeč

The therapeutic potential of interleukin (IL)-2 in cancer treatment has been known for decades, yet its widespread adoption in clinical practice remains limited. Recently, chimeric proteins of an anti-PD-1 antibody and suboptimal IL-2 variants were shown to stimulate potent antitumor and antiviral immunity by inducing unique effector CD8+ T cells in mice. A similar subset of cytotoxic T cells is induced by depletion of regulatory T cells (Tregs), suggesting IL-2 sequestration as a major mechanism through which regulatory T cells suppress activated CD8+ T cells. Here, we present our view of how IL-2-based biologicals can boost the antitumor response at a cellular level, and propose that the role of Tregs following such treatments may have been previously overestimated.

• Klíčová slova
• IL-2, PD-1, cancer, cytotoxic T cells, immunotherapy, regulatory T cell,
• MeSH
• CD8-pozitivní T-lymfocyty * MeSH
• cytotoxické T-lymfocyty MeSH
• fenotyp MeSH
• imunoterapie MeSH
• interleukin-2 * terapeutické užití   metabolismus   MeSH
• myši MeSH
• regulační T-lymfocyty MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• interleukin-2 * MeSH