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Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function and expression in the tumor microenvironment make them attractive targets for immunotherapy, leading to the development of IL-2/IL-2R-targeted therapeutic strategies. However, the dynamic interplay between IL-2/IL-2R and various immune cells and their dual roles in promoting immune activation and tolerance presents a complex landscape for clinical exploitation. This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their therapeutic manipulation in cancer. It underlines the necessity to balance the anti-tumor activity with regulatory T-cell expansion and evaluates strategies such as dose optimization and selective targeting for enhanced therapeutic effectiveness. The article explores recent advancements in the field, including developing genetically engineered IL-2 variants, combining IL-2/IL-2R-targeted therapies with other cancer treatments, and the potential benefits of a multidimensional approach integrating molecular profiling, immunological analyses, and clinical data. The review concludes that a deeper understanding of IL-2/IL-2R interactions within the tumor microenvironment is crucial for realizing the full potential of IL-2-based therapies, heralding the promise of improved outcomes for cancer patients.

The IL-2 family of cytokines act via receptor complexes that share the interleukin-2 receptor gamma common (IL-2Rγc) chain to play key roles in lymphopoiesis. Inactivating IL-2Rγc mutations results in severe combined immunodeficiency (SCID) in humans and other species. This study sought to generate an equivalent zebrafish SCID model. The zebrafish il2rga gene was targeted for genome editing using TALENs and presumed loss-of-function alleles analyzed with respect to immune cell development and impacts on intestinal microbiota and tumor immunity. Knockout of zebrafish Il-2rγc.a resulted in a SCID phenotype, including a significant reduction in T cells, with NK cells also impacted. This resulted in dysregulated intestinal microbiota and defective immunity to tumor xenotransplants. Collectively, this establishes a useful zebrafish SCID model.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have shown considerable promise as a therapeutic modality in oncology. Despite their ability to target stem-like CD8 T cells and give rise to exhaustion-fated effector CD8 T cells, a significant subset of patients do not respond or eventually develop resistance, highlighting the need for more efficacious therapies. Eciskafusp alfa (PD1-IL2v) is a novel immunocytokine, engineered for avidity-driven, -delivery of IL-2R agonism to PD-1 cells. This study provides a comprehensive characterization of PD1-IL2v's target landscape using matched peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) from patients across seven solid tumor indications. We confirmed that the TIL compartment is significantly enriched with both stem-like CD8 T cells and immunosuppressive regulatory T cells (Tregs). Notably, PD-1 receptor density was increased up to three-fold on CD8 TILs compared to PBMCs, establishing the basis for preferential intra-tumoral targeting. assays demonstrated that PD1-IL2v preferentially targets CD8 TIL subsets (stem-like and effector) over Tregs. This preferential targeting translated into superior biological activity, with PD1-IL2v inducing higher STAT5 phosphorylation (STAT5-P) in stem-like and effector CD8 T cells compared to Tregs, confirming the intended -targeting and enhanced IL-2R agonism. These findings provide translational validation for PD1-IL2v's mechanism, demonstrating selective intra-tumoral immune stimulation while minimizing Treg activation. This characterization identifies PD-1 receptor density and subset prevalence as critical factors for drug activity and represents potentially useful biomarkers for predicting patient responsiveness and guiding patient selection.

The tumor immune microenvironment (TME) plays a key role in the development of hepatocellular carcinoma (HCC). As the important components of TME, interleukin-2 (IL-2) mediates immune responses by specifically binding to the interleukin-2 receptor (IL-2R). This study aimed to explore the role of IL-2R in HCC development and provided possible clinical implications in HCC prognosis and treatment. The IL-2R genetic data were acquired from publicly available TCGA and CCLE databases. Data processing and analysis, including construction of the prognostic model and evaluation of immune status in HCC, were performed on Xiantao platform by using statistical methods including the Wilcoxon test, Cox regression analysis, correlation analysis. GEPIA2 was used to explore the relationship between IL-2R genes expression and clinical stages, while genetic variations in IL-2R subunits in HCC were determined using cBioPortal. The IL-2Rα co-expression gene analysis was conducted on the LinkedOmics database. Enzyme-linked immunosorbent assay (ELISA), colorimetric method, and flow cytometric method were used to analyze peripheral blood samples from patients with HCC. A prognostic risk model was established by incorporating IL-2Rα, IL-2Rβ, and IL-2Rγ expression. The infiltration levels of B cell memory, T cell regulatory cells (Tregs), and immune checkpoints (PDCD1, CTLA4, CD274 and TIGIT) were significantly elevated in high-risk group of the risk model. Additionally, sIL-2Rα levels were positively correlated with tumor-specific growth factor (TSGF) and Tregs in the peripheral blood of HCC patients. The prognostic risk model based on IL-2R subunits may play a role in the regulation of immune function within the HCC tumor microenvironment. Besides, IL-2Rα may act as a more important role in HCC development among the three IL-2R subunits. Further research will be needed to verify these initial findings. Overall, these results may provide important insights in clinical prognosis and therapeutic strategies for HCC.

Accurate screening of COVID-19 infection status for symptomatic patients is a critical public health task. Although molecular and antigen tests now exist for COVID-19, in resource-limited settings, screening tests are often not available. Furthermore, during the early stages of the pandemic tests were not available in any capacity. We utilized an automated machine learning (ML) approach to train and evaluate thousands of models on a clinical dataset consisting of commonly available clinical and laboratory data, along with cytokine profiles for patients (n = 150). These models were then further tested for generalizability on an out-of-sample secondary dataset (n = 120). We were able to develop a ML model for rapid and reliable screening of patients as COVID-19 positive or negative using three approaches: commonly available clinical and laboratory data, a cytokine profile, and a combination of the common data and cytokine profile. Of the tens of thousands of models automatically tested for the three approaches, all three approaches demonstrated > 92% sensitivity and > 88 specificity while our highest performing model achieved 95.6% sensitivity and 98.1% specificity. These models represent a potential effective deployable solution for COVID-19 status classification for symptomatic patients in resource-limited settings and provide proof-of-concept for rapid development of screening tools for novel emerging infectious diseases.

Signaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

Syphilis is a sexually transmitted disease (STD) caused by ( ) which could progress to neurosyphilis affecting the nervous system. However, the pathogenesis of neurosyphilis remain unknown. In addition, current diagnosis of neurosyphilis is mainly based on serological tests and cerebrospinal fluid (CSF) analysis, with limitations in terms of sensitivity and specificity. From April 2021 to April 2023, 129 patients with syphilis were enrolled and divided into the non-neurosyphilis group (common syphilis, CS, n=19), asymptomatic neurosyphilis group (AN, n=77), symptomatic neurosyphilis group (NS, n=33) and a control group (n=15). Forty-eight cytokines/chemokines in the CSF samples were measured and analysed in combination with clinical indices. Feature selections were further analysed for the using different machine learning model for the diagnosis and progression predicting of neurosyphilis. Machine learning-based feature selection identified a three-cytokine panel (RANTES, MIP-1β, and IL-3) that effectively distinguished syphilis patients from controls (AUC = 0.869, 95% CI: 0.821-0.917). For prediction of symptomatic neurosyphilis progression, IL-2Rα emerged as the optimal standalone biomarker, achieving an AUROC of 0.843 (95% CI: 0.784-0.902) for discriminating asymptomatic from symptomatic disease. Multivariable analysis confirmed IL-2Rα retained independent discriminatory power after adjusting for age (multivariable AUC = 0.876, 95% CI: 0.827-0.925). Age-stratified ROC analysis revealed IL-2Rα maintains robust diagnostic utility across all adult age groups, with optimal Youden-derived cut-offs of 21.82 U/mL (sensitivity 100.0%, specificity 85.7%, AUC 0.939) for 35-45 years; 25.48 U/mL (sensitivity 83.3%, specificity 88.9%, AUC 0.889) for 45-55 years; and 24.54 U/mL (sensitivity 73.7%, specificity 84.6%, AUC 0.789) for >55 years. The combination of IL-2Rα and IP-10 significantly improved predictive accuracy within specific age strata, achieving AUCs of 0.949 (35-45 years), 1.000 (45-55 years), and 0.814 (>55 years) when distinguishing symptomatic from asymptomatic neurosyphilis. In conclusion, IL-2Rα and IP-10 represent promising predictive biomarkers for neurosyphilis progression, with their combined application achieving high diagnostic accuracy for distinguishing symptomatic from asymptomatic disease. These findings establish a foundation for CSF cytokine-guided risk stratification in syphilis patients, although prospective validation in larger, age-matched cohorts is warranted to optimize clinical cut-offs and confirm generalizability across diverse populations.

Interleukin 2 receptor alpha chain (IL-2Rα or CD25) deficiency (OMIM #606367) is an immune dysregulation disorder segregating in autosomal recessive form. The disease is caused by biallelic variants in the IL-2Rα gene encoding IL-2Rα also known as CD25 protein. IL-2Rα combines with γ and β chains of interleukin 2 receptor to form a functional interleukin 2 receptor (IL-2R). In the present study, we identified a Pakistani family presenting a unique presentation of IL-2Rα deficiency. Clinical whole exome sequencing revealed a novel splice donor site variant (NM_001378789.1 (NP_001365718); c.64 + 1G > A) in the IL-2Rα gene. American College of Medical Genetics (ACMG) guidelines interpreted the identified variant as likely pathogenic. The IL-2Rα gene mutation usually presents with autoimmunity and immunodeficiency but in our patient, it presents with congenital diarrhea, metabolic crisis, and strong family history of death in infancy due to the similar complications. Her congenital diarrhea is attributed to autoimmunity in the form of autoimmune enteropathy and eczema. The laboratory findings revealed severe metabolic acidosis hypokalemia and elevated lactate and ammonia levels. This is a new presentation of IL-2Rα gene mutation. The present study highlights the importance of clinical whole exome sequencing in the correct diagnosis of congenital disorders. The study will also help clinical geneticists for genetic counseling and prevention of the disease in the affected family.

As T and NK cell exhaustion is attributed to increased expression of immune checkpoints and decreased production of proliferative cytokines by these cells, immune checkpoint-targeted delivery of proliferative cytokines might induce robust and sustained antitumor immune responses. Here, the expression profile of NKG2A was first found to be narrower than that of PD-1 in tumor-infiltrated immune cells. Moreover, unlike PD-1, NKG2A was predominantly co-expressed with IL-2Rβγ in tumor-infiltrated CD8 T and NK cells, but not in Tregs, suggesting that NKG2A might be an ideal target for delivery of IL-2Rβγ agonists to overcome T and NK exhausting. For NKG2A-targeted delivery of an IL-2Rβγ agonist, a single molecule of de novo designed N215 endowed with Immunoglobin G(IgG)-binding ability was coupled to an antibody against NKG2A (αNKG2A) to produce αNKG2A-N215. NKG2A- and IL-2Rβγ-binding were well preserved in αNKG2A-N215, allowing αNKG2A-N215 to act as both an immune checkpoint inhibitor and a T and NK cell stimulator. Intravenously injected αNKG2A-N215 predominantly induced expansion of tumor-infiltrated CD8 T and NK cells while showing little stimulation of Tregs. Compared with the separate combination using αNKG2A and N215, αNKG2A-N215 exerted a greater antitumor effect in mice bearing MC38 or B16/F1 tumors. 50% of mice bearing MC38 tumors were cured by αNKG2A-N215, and long-term immunological memory against the tumor was induced in these mice. These results indicate that NKG2A is another ideal target for delivery of an IL-2Rβγ agonist, and αNKG2A-N215, with specificities for both NKG2A and IL-2Rβγ, might be developed as a novel agent for immunotherapy.