Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(1), P. e010405 - e010405

Published: Jan. 1, 2025

Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, date there are few preclinical models accurately represent these disparate disease scenarios. Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, OX40 agonism we were able generate tumor conflicting responses, where head neck squamous cell carcinoma (HNSCC) respond pancreatic ductal adenocarcinoma (PDAC) progresses. Results By modeling states, find regulatory T cells (Tregs) expanded in PDAC tumors undergoing treatment, constraining reactive CD8 activity. Consequently, depletion Tregs restores therapeutic efficacy our treatment abrogates disparity between models. Moreover, show through heterotopic implantations site development defines therapy, as implantation HNSCC into pancreas resulted comparable levels progression. Conclusions This work highlights complexity combining immunotherapies within microenvironment (TME) further immune non-immune components TME an intrinsic feature suppression.

Language: Английский

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Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy

OncoImmunology, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 15, 2025

Immune checkpoint blockade (ICB) has significantly improved the survival for many patients with advanced malignancy. However, fewer than 50% of benefit from ICB, highlighting need more effective immunotherapy options. High-dose interleukin-2 (HD IL-2) immunotherapy, which is approved metastatic melanoma and renal cell carcinoma, stimulates CD8+ T cells NK can generate durable responses in a subset patients. Moreover, HD IL-2 may have potential efficacy whose disease progressed following ICB plays vital role expanding tumor-infiltrating lymphocyte (TIL) TIL therapy. Despite its potential, use limited by severe toxicities such as hypotension vascular leak syndrome. Additionally, only few achieve good outcome after To address these challenges, numerous next-generation receptor (IL-2 R) agonists been developed to exhibit treatment effects while minimizing adverse events. This review will explore biology, clinical application therapy, development novel R cancer immunotherapy.

Language: Английский

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Evolving Paradigms in the Treatment of Oligometastatic Pancreatic Ductal Adenocarcinoma

Journal of Gastrointestinal Cancer, Journal Year: 2025, Volume and Issue: 56(1)

Published: Jan. 18, 2025

Language: Английский

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Based on the immune system: the role of the IL-2 family in pancreatic disease

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 31, 2025

The IL-2 family, consisting of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, is a key regulator the immune response. As an important endocrine digestive organ, function pancreas regulated by system. Studies have shown that each cytokine family influences occurrence development pancreatic diseases participating in regulation In this paper, we review structural functional characteristics members, focus on their molecular mechanisms including acute pancreatitis, chronic pancreatitis cancer, highlight importance related proteins response disease progression, which will provide valuable insights for new biomarkers diseases, early diagnosis assessment severity, therapeutic regimens. study are summarized following sections.

Language: Английский

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Development of Novel Short Peptide Inhibitor Targeted to Immune Checkpoint PD-1 LBD

International Journal of Peptide Research and Therapeutics, Journal Year: 2025, Volume and Issue: 31(3)

Published: March 7, 2025

Language: Английский

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Prognostic implications and characterization of tumor-associated tertiary lymphoid structures genes in pancreatic cancer

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 10, 2025

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive cancers, with rising incidence and limited responsiveness to immunotherapy due its highly suppressive tumor microenvironment (TME). Tertiary lymphoid structures (TLS), ectopic formation of immune cells, are linked better prognosis improved responses in PDAC. Understanding TLS's role PDAC could enhance effectiveness. This study integrated transcriptomic clinical data from 310 patients GEO database. We performed consensus clustering using tumor-associated TLS (TA-TLS) genes, identifying three distinct molecular subtypes. Single-sample gene set enrichment analysis (ssGSEA) was then employed calculate a score for each patient, allowing TLS-based evaluation. Key prognostic genes were identified an iterative LASSO method, leading construction risk assessment model, which validated across independent cohorts. further analyzed single-cell RNA sequencing (scRNA-seq), visualized key expression, protein expression through immunohistochemistry (IHC). Additionally, we explored effects DNASE1L3 on cell proliferation migration, immune-related functions Gene Set Enrichment Analysis (GSEA) multiplex cytokine analysis. Consensus revealed subtypes significant differences prognosis, TA-TLS TME features. The effectively stratified into high low groups, correlating survival outcomes characteristics. Our cohorts, reliably predicted patient outcomes. Validation studies showed lower IL33 tissues. scRNA-seq confirmed associations cells. overexpression inhibited indicating increased activity. elucidated profile PDAC, constructed gene-based scoring system, developed related model. also potential antitumor mechanisms providing evidence new insights enhancing TLS-targeted strategies

Language: Английский

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A comprehensive review on targeting diverse immune cells for anticancer therapy: beyond immune checkpoint inhibitors

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: 210, P. 104702 - 104702

Published: March 22, 2025

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired continue to limit their efficacy for many patients. To address enhance the anti-tumor activity within tumor microenvironment (TIME), numerous therapeutic strategies targeting both innate adaptive cells emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), macrophages (CAR-Ms) or natural killer cell (CAR-NK) therapy, colony stimulating factor 1 (CSF1R) inhibitors, dendritic (DC) vaccines, toll-like (TLR) agonists, cytokine therapies, chemokine inhibition. approaches underscore significant potential of TIME in treatment. This article provides a comprehensive up-to-date review mechanisms action various TIME, as well each type, aiming deepen understanding potential.

Language: Английский

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Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(3), P. e010650 - e010650

Published: March 1, 2025

Background Owing to their roles in promoting T cell and natural killer (NK) activation proliferation, interleukins-2 (IL-2) interleukins-15 (IL-15) have been pursued as promising pathways target cancer immunotherapy. Nonetheless, wider therapeutic application has hampered by severe dose-limiting toxicities including systemic cytokine release organ edema for IL-2, inconvenient intratumoral administration IL-15. To address these safety issues, we generated IL-2R/IL-15R×TAA (tumor-associated antigen) bispecific antibody (bsAb) pairs selectively activate IL-2R signaling the tumor microenvironment. Methods Each bsAb pair is composed of one targeting CD122 a TAA epitope, other CD132 same or different epitope. In vitro assays were performed characterize IL-2R/IL-15R agonistic activity pairs, well capacity enhance T-cell-mediated killing + malignant cells. Using syngeneic mouse model, vivo biological toxicity assessed comparison with IL-2. The antitumor was combination an anti-mouse programmed death protein 1 (mPD-1) monoclonal antibody. Results We demonstrated two TAAs (human epidermal growth factor receptor 2 (HER2) mesothelin (MSLN)) that CD122×TAA/CD132×TAA mediate effective immune cells exclusively presence hMSLN-MC38 tumor-bearing mice, CD122×MSLN-1/CD132×MSLN-2 promotes selective expansion NK central memory CD8 inside without inducing release, well-known manifestations IL-2 associated toxicity. checkpoint inhibitor anti-mPD-1, boosts accumulation effector cells, leading favorable CD4 regulatory ratio more robust inhibition growth. Conclusions Overall, findings suggest this innovative approach effectively leverages IL-15 while minimizing toxicities. This dual format holds potential broader immune-activating pathways.

Language: Английский

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Orchestrating T and NK cells for tumor immunotherapy via NKG2A-targeted delivery of a de novo designed IL-2Rβγ agonist

Drug Delivery, Journal Year: 2025, Volume and Issue: 32(1)

Published: April 1, 2025

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

Language: Английский

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Dual Facets of Ionizing Radiation in Cancer Therapy: Immunomodulation and Immunosuppression

Published: Jan. 1, 2025

Language: Английский

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