Blockade of TGF-β and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses DOI Creative Commons

Jacob Kment,

Daniel Newsted,

Stephanie Young

et al.

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 130(12), P. 2003 - 2015

Published: April 15, 2024

Abstract Background Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels transforming growth factor-β (TGF-β) ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade TGF-β and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour responses preclinical HGSC models. Methods BA is a first-in-class bifunctional inhibitor PD-L1, was tested for effects on overall survival altered TIME syngeneic Results Using mouse ID8-derived model IFNγ-inducible expression, treatments significantly reduced development burden. depleted VEGF ascites, skewed the towards cytotoxicity compared control. In BR5 model, increased tumour-infiltrating CD8 T cells effector memory cytotoxic markers, as well cytolytic NK cells. Extended produced ∼50% BA-cured mice that were protected from re-challenge. These had peritoneal T-effector controls. Conclusions Our studies advanced models support further testing an improved option patients cancer.

Language: Английский

Anti-TGF-β/PD-L1 bispecific antibody synergizes with radiotherapy to enhance antitumor immunity and mitigate radiation-induced pulmonary fibrosis DOI Creative Commons
Yuze Wu,

Yuheng Yan,

Yarong Guo

et al.

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: March 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.

Language: Английский

Citations

2
The application and research progress of anti-angiogenesis therapy in tumor immunotherapy DOI Creative Commons
Jingyao Tu, Hang Liang, Chunya Li

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 2, 2023

Tumor immunotherapy, as the focus of scientific research and clinical tumor treatment in recent years, has received extensive attention. Due to its remarkable curative effect fewer side effects than traditional treatments, it significant benefits for various advanced cancers can improve cancer patient survival long term. Currently, most patients cannot benefit from some may experience recurrence drug resistance even if they achieve remission overcome. Numerous studies have shown that abnormal angiogenesis state tumors lead immunosuppressive microenvironment, which affects efficacy immunotherapy. Actually, application anti-angiogenesis drugs normalize vessel been widely confirmed basic research. This review not only discusses risk factors, mechanisms, normalized on immune environment, but summarizes latest progress immunotherapy combined with anti-angiogenic therapy. We hope this provides an applied reference synergistic

Language: Английский

Citations

30
Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer DOI Creative Commons
Hao Zhang, Shuangli Zhu, Haiting Zhou

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 16, 2023

Background Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme encoded in the nucleus. It plays significant role regulation of glucose, nucleic acid, and folate metabolism, maintains redox balance cells. The present study aimed at elucidating potential function mechanisms MTHFD2 explored correlation between ferroptosis triple-negative breast cancer. Methods expression, survival analysis, clinical were performed using data from various online databases including TCGA, GEO, HPA, GTEX, Kaplan–Meier Plotter, PrognoScan, UALCAN databases. Genomic alterations CNV analysis cBioPortal GSCA Potential functions by enrichment analysis. tumor microenvironment was identified TIMER database. In vitro , RT-qPCR western blot assays utilized to identify expression knockdown effects CCK8, cell wound healing, transwell, flow cytometry used TNBC MDA, GSH detection, ferroptosis. Western measure protein all target genes. Results levels up-regulated majority cancers particularly TNBC, which higher indicated poorer prognosis. Enrichment analyses showed that involved tumor-related biological processes. found strongly correlate with multiple immune infiltration. suppresses proliferation, apoptosis, migration, invasion addition, significantly enhanced intracellular ROS lipid peroxidation decreased GSH. expressions SLC7A11, GPX4, NRF2 down-regulated knockdown. Conclusion could be crucial molecular biomarker for predicting patient prognosis novel therapeutic TNBC. regulatory gene

Language: Английский

Citations

28
Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1 DOI Creative Commons
Keywan Mortezaee, Jamal Majidpoor

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 163, P. 114824 - 114824

Published: May 2, 2023

CD8+ T cells are the front-line defensive against cancer. Reduced infiltration and effector function of occurs in cancer is contributed to defective immunity immunotherapy resistance. Exclusion exhaustion two key factors associated with reduced durability immune checkpoint inhibitor (ICI) therapy. Initially activated upon exposure chronic antigen stimulation or immunosuppressive tumor microenvironment (TME) acquire a hyporesponsive state that progressively lose their function. Thus, strategy look for cell Targeting such can define promising supplementary approach patients receiving anti-programmed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) Recently, bispecific antibodies developed PD-(L)1 dominant factor within TME, representing higher safety profile exerting more desired outcomes. The focus this review discuss about promoters deficient addressing ICI

Language: Английский

Citations

25
Nanoparticle-based immunoengineering strategies for enhancing cancer immunotherapy DOI

Bao-Toan Nguyen Dang,

Taeg Kyu Kwon, Sooyeun Lee

et al.

Journal of Controlled Release, Journal Year: 2023, Volume and Issue: 365, P. 773 - 800

Published: Dec. 14, 2023

Language: Английский

Citations

23
Targeting tumor-infiltrating tregs for improved antitumor responses DOI Creative Commons

Diyuan Qin,

Yugu Zhang,

Pei Shu

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: March 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.

Language: Английский

Citations

14
The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling DOI Creative Commons
Tianye Li,

Mengke Niu,

Jianwei Zhou

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 12, 2024

Abstract The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become focal point cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result T exhaustion and evasion, fostering progression. advent PD-1/PD-L1 inhibitor demonstrated clinical success by unleashing from exhaustion. Nevertheless, challenges such as resistance adverse effects have spurred exploration innovative strategies, with bispecific antibodies (BsAbs) emerging promising frontier. BsAbs offer multifaceted approach to immunotherapy simultaneously targeting other regulatory molecules. We focus recent advancements therapy particular emphasis development potential BsAbs, especially solid tumors. Various BsAb products PD-1 are discussed, highlighting their unique mechanisms action therapeutic potential. Noteworthy examples include anti-TGFβ × PD-L1, anti-CD47 anti-VEGF anti-4-1BB anti-LAG-3 anti-PD-1 CTLA-4 BsAbs. Besides, we summarize ongoing studies evaluating efficacy safety these agents. By unraveling intricacies microenvironment harnessing synergistic anti-PD-1/PD-L1 there exists elevate precision immunotherapy, ultimately enabling personalized treatment strategies tailored individual patient profiles.

Language: Английский

Citations

14
Tumor battlefield within inflamed, excluded or desert immune phenotypes: the mechanisms and strategies DOI Creative Commons
Siwei Zheng,

Wenwen Wang,

Lesang Shen

et al.

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Aug. 6, 2024

Abstract The tumor microenvironment demonstrates great immunophenotypic heterogeneity, which has been leveraged in traditional immune-hot/cold categorization based on the abundance of intra-tumoral immune cells. By incorporating spatial contexture, immunophenotype was further elaborated into immune-inflamed, immune-excluded, and immune-desert. However, mechanisms underlying these different phenotypes are yet to be comprehensively elucidated. In this review, we discuss how cells interact collectively shape landscape from perspectives cells, extracellular matrix, cancer metabolism, summarize potential therapeutic options according distinct immunophenotypes for personalized precision medicine.

Language: Английский

Citations

14
Bispecific antibody targeting TGF-β and PD-L1 for synergistic cancer immunotherapy DOI Creative Commons
Tianye Li, Xinrun Wang,

Mengke Niu

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 13, 2023

The PD-1/PD-L1 signaling pathway plays a crucial role in cancer immune evasion, and the use of anti-PD-1/PD-L1 antibodies represents significant milestone immunotherapy. However, low response rate observed unselected patients development therapeutic resistance remain major obstacles to their clinical application. Accumulating studies showed that overexpressed TGF-β is another immunosuppressive factor apart from traditional checkpoints. Actually, effects PD-1 pathways are independent interactive, which work together contributing evasion cell. It has been verified blocking PD-L1 simultaneously could enhance efficacy monoclonal antibody overcome its treatment resistance. Based on bispecific or fusion protein technology, multiple bifunctional have developed. In preclinical studies, these updated exhibited potent anti-tumor activity, superior monotherapies. review, we summarized advances targeting We believe next-generation checkpoint inhibitors would substantially alter paradigm, especially anti-PD-1/PD-L1-resistant patients.

Language: Английский

Citations

21
Bispecific antibodies targeting CTLA-4: game-changer troopers in cancer immunotherapy DOI Creative Commons
Pooya Farhangnia, Shamim Mollazadeh Ghomi, Mahzad Akbarpour

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 27, 2023

Antibody-based cancer immunotherapy has become a powerful asset in the arsenal against malignancies. In this regard, bispecific antibodies (BsAbs) are ground-breaking novel approach therapy of cancers. Recently, BsAbs have represented significant advancement improving clinical outcomes. designed to target two different antigens specifically. Over hundred various BsAb forms currently exist, and more constantly being manufactured. An antagonistic regulator T cell activation is cytotoxic lymphocyte-associated protein 4 (CTLA-4) or CD152, second counter-receptor for B7 family co-stimulatory molecules was introduced 1996 by Professor James P. Allison colleagues. Contrary explosive success dual immune checkpoint blockade treating cancers, major hurdle still yet persist that immune-related adverse events (irAEs) observed combining inhibitors (ICIs) monoclonal such as ipilimumab (anti-CTLA-4) nivolumab (anti-PD-1). A promising strategy overcome using BsAbs. This article will summarize targeting CTLA-4, their applications immunotherapy, relevant trial advances. We also discuss pre-clinical rationale these BsAbs, provide current landscape field.

Language: Английский

Citations

20