Unleashing the Power of immune Checkpoints: A new strategy for enhancing Treg cells depletion to boost antitumor immunity

International Immunopharmacology, Год журнала: 2025, Номер 147, С. 113952 - 113952

Опубликована: Янв. 6, 2025

Regulatory T (Treg) cells, immunosuppressive CD4+ can impede anti-tumor immunity, complicating cancer treatment. Since their discovery, numerous studies have been dedicated to understand Treg cell biology, with a focus on checkpoint pathways' role in generation and function. Immune checkpoints, such as PD-1/PD-L1, CTLA-4, TIGIT, TIM-3, OX40, are pivotal controlling expansion activity the tumor microenvironment (TME), affecting ability suppress immune responses. This review examines complex relationship between these checkpoints Tregs TME, how they influence immunity. We also discuss therapeutic potential of targeting enhance including use blockade (ICB) therapies novel approaches CCR8-targeted therapies. Understanding interaction cells lead more effective immunotherapeutic strategies, combining inhibitors, improve patient outcomes

Язык: Английский

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Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures

Cell Reports Medicine, Год журнала: 2025, Номер unknown, С. 101934 - 101934

Опубликована: Фев. 1, 2025

Highlights•mTLSs are predictive of response to ICIs in NSCLC•Two CAF subsets within the TME key determinants primary resistance ICIs•FAP+αSMA+ CAFs correlate with inflammatory and exhaustion CD8+ T cells•MYH11+αSMA+ favor an immunosuppressive CD4+ Treg cell infiltrationSummaryEffectiveness immune checkpoint inhibitors (ICIs) non-small lung cancer (NSCLC) has been linked presence mature tertiary lymphoid structures (mTLSs) tumor microenvironment (TME). However, only a subset mTLS-positive NSCLC derives benefit, thus highlighting need unravel ICI determinants. The comprehensive analysis ICI-treated patients (n = 509) from Bergonié Institute Profiling (BIP) study (NCT02534649) reveals that mTLSs correlates improved clinical outcomes, independently programmed death ligand 1 (PD-L1) expression genomic features. Employing spatial transcriptomics alongside multiplex immunofluorescence (mIF), we show two distinct cancer-associated fibroblasts (CAFs) essential factors mediating NSCLC. These associated exclusion, exhaustion, increased regulatory infiltration, underscoring TME. Our highlights pivotal role specific thwarting ICIs, proposing new therapeutic targets enhance immunotherapy efficacy.Graphical abstract

Язык: Английский

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Anti-TGF-β/PD-L1 bispecific antibody synergizes with radiotherapy to enhance antitumor immunity and mitigate radiation-induced pulmonary fibrosis

Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)

Опубликована: Март 5, 2025

Despite the success of immune checkpoint inhibitors (ICIs) in multiple malignant tumors, a significant proportion patients remain unresponsive to treatment. Radiotherapy (RT) elicits immunogenic antitumor responses but concurrently activates several evasion mechanisms. Our earlier research demonstrated efficacy YM101, an anti-TGF-β/PD-L1 bispecific antibody, stroma-rich tumors. Nevertheless, YM101 has reduced effectiveness non-inflamed tumors characterized by poor cell infiltration. This study investigated potential synergy between RT and overcoming immunotherapy resistance mitigating RT-induced pulmonary fibrosis. The activity survival outcomes plus treatment vivo were explored murine tumor models. Furthermore, inhibition metastases was assessed metastasis model. impact on dendritic (DC) maturation quantified flow cytometry, whereas cytokine chemokine secretions measured ELISA. To comprehensively characterize changes microenvironment, we utilized combination methods, including IHC staining, multiplex inmunofluorecence RNA sequencing. Additionally, evaluated significantly inhibited growth, prolonged compared with monotherapies promoted DC dose-dependent manner increased proinflammatory cytokines. Mechanistically, simultaneously infiltration activation intratumoral DCs tumor-infiltrating lymphocytes reshaped microenvironment landscape. Notably, attenuated both peritumoral fibrosis findings suggest that combined enhances immunity overcomes preclinical models, while showing therapy demonstrates promise ICI resistance, potentially sparing normal tissue, thereby providing strong rationale for further clinical investigations.

Язык: Английский

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Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

Immunity, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Drug conjugates for targeting regulatory T cells in the tumor microenvironment: guided missiles for cancer treatment

Experimental & Molecular Medicine, Год журнала: 2023, Номер 55(9), С. 1996 - 2004

Опубликована: Сен. 1, 2023

Within the tumor microenvironment (TME), regulatory T cells (Tregs) play a key role in suppressing anticancer immune responses; therefore, various strategies targeting Tregs are becoming important for therapy. To prevent side effects of nonspecific Treg depletion, such as immunotherapy-related adverse events (irAEs), therapeutic that specifically target TME being investigated. Tumor-targeting drug conjugates efficient drugs which cytotoxic payload is assembled into carrier binds via linker. By allowing to act selectively on cells, this approach has advantage increasing effect and minimizing immunotherapy. Antibody-drug conjugates, immunotoxins, peptide-drug small interfering RNA developed Treg-targeting conjugates. In review, we discuss themes recent advances TME, well future design successful use

Язык: Английский

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Unveiling the Immune Microenvironment’s Role in Breast Cancer: A Glimpse into Promising Frontiers

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(20), С. 15332 - 15332

Опубликована: Окт. 18, 2023

Breast cancer (BC), one of the most widespread and devastating diseases affecting women worldwide, presents a significant public health challenge. This review explores emerging frontiers research focused on deciphering intricate interplay between BC cells immune microenvironment. Understanding role system in is critical as it holds promise for novel therapeutic approaches precision medicine strategies. delves into current literature regarding microenvironment's contribution to initiation, progression, metastasis. It examines complex mechanisms by which interact with various cell populations, including tumor-infiltrating lymphocytes (TILs) tumor-associated macrophages (TAMs). Furthermore, this highlights impact immune-related factors, such cytokines checkpoint molecules. Additionally, comprehensive analysis sheds light potential biomarkers associated response BC, enabling early diagnosis prognostic assessment. The implications targeting microenvironment are also explored, encompassing immunotherapeutic strategies combination therapies enhance treatment efficacy. significance lies its pave way interventions, providing clinicians researchers essential knowledge design targeted personalized regimens patients.

Язык: Английский

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Enhancing cancer immunotherapy: Nanotechnology-mediated immunotherapy overcoming immunosuppression

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(9), С. 3834 - 3854

Опубликована: Июнь 3, 2024

Immunotherapy is an important cancer treatment method that offers hope for curing patients. While immunotherapy has achieved initial success, a major obstacle to its widespread adoption the inability benefit majority of The success or failure closely linked tumor's immune microenvironment. Recently, there been significant attention on strategies regulate tumor microenvironment in order stimulate anti-tumor responses immunotherapy. distinctive physical properties and design flexibility nanomedicines have extensively utilized target cells (including tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor (MDSCs), fibroblasts (TAFs)), offering promising advancements In this article, we reviewed aimed at targeting various focus models are based nanomedicines, with goal inducing enhancing improve It worth noting combining other treatments, such as chemotherapy, radiotherapy, photodynamic therapy, can maximize therapeutic effects. Finally, identified challenges nanotechnology-mediated needs overcome more effective nanosystems.

Язык: Английский

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Targeting tumor-infiltrating tregs for improved antitumor responses

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Март 4, 2024

Immunotherapies have revolutionized the landscape of cancer treatment. Regulatory T cells (Tregs), as crucial components tumor immune environment, has great therapeutic potential. However, nonspecific inhibition Tregs in therapies may not lead to enhanced antitumor responses, but could also trigger autoimmune reactions patients, resulting intolerable treatment side effects. Hence, precision targeting and tumor-infiltrating is paramount importance. In this overview, we summarize characteristics subpopulations within microenvironment their inhibitory mechanisms responses. Furthermore, discuss current major strategies regulatory cells, weighing advantages limitations, representative clinical trials We believe that developing specifically target suppress holds promise for advancing immune-based therapies.

Язык: Английский

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Metabolism/Immunity Dual‐Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate‐Excretion Inhibition and PD‐1/PD‐L1 Blockade

Advanced Science, Год журнала: 2024, Номер 11(18)

Опубликована: Март 9, 2024

Abstract Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient infiltration of T cells severely impede the progress glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting expression glucose transporter 1 (GLUT1) can facilitate prevention lactate excretion from glycolysis, which significantly alleviates lactate‐driven ITM by reducing tumor‐associated macrophages (TAMs) regulatory (Tregs). Simultaneously, findings show generated inflammatory cytokine IFN‐γ during immune activation aggravates escape upregulating checkpoint programmed death‐ligand (PD‐L1) in TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY‐876 PD‐1/PD‐L1 blocker BMS‐1 (Gel@B‐B) for dual‐regulation metabolism immunity GBM developed. Consequently, situ injection Gel@B‐B delays growth prolongs survival orthotopic mouse model. By actively exposing antigens to antigen‐presenting cells, vaccine combined found increase fraction effector (Th1/CTLs) microenvironment, thereby remarkably mitigating recurrence long‐term. This study may provide promising strategy

Язык: Английский

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Role of gut microbiota in regulating immune checkpoint inhibitor therapy for glioblastoma

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июнь 10, 2024

Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong patient survival. With the deepening of research, it has been found that gut microbiota plays certain role in GBM, can directly or indirectly affect efficacy immune checkpoint inhibitors (ICIs) various ways. (1) The metabolites produced by host’s homeostasis, these function distribution cells, promote inhibit inflammatory responses, phenotype, angiogenesis, response, cell infiltration GBM thereby affecting effectiveness ICIs. (2) Some members may reverse T inhibition, increase anti-tumor activity, ultimately improve ICIs targeting specific immunosuppressive cytokines. (3) participate metabolic process drugs, which degrade, transform, produce metabolites, effective concentration bioavailability drugs. Optimizing structure help (4) also regulate status through axis communication, progression therapeutic response to (5) Given importance for ICI therapy, researchers have begun exploring use fecal transplantation (FMT) transplant healthy optimized patients, order their enhance therapy. Preliminary studies suggest FMT therapy some patients. In summary, crucial regulating with deeper understanding relationship between tumor immunity, expected develop more precise personalized strategies prognosis.

Язык: Английский

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