Changing the location of proteins on the cell surface is a promising strategy for modulating T cell functions DOI
Marianne Strazza,

Ruijiang Song,

Shannon Hiner

et al.

Immunology, Journal Year: 2024, Volume and Issue: 173(2), P. 248 - 257

Published: July 1, 2024

Abstract Targeting immune receptors on T cells is a common strategy to treat cancer and autoimmunity. Frequently, this accomplished through monoclonal antibodies targeting the ligand binding sites of stimulatory or inhibitory co‐receptors. Blocking prevents downstream signalling modulates specific cell functions. Since 1985, FDA has approved over 100 against receptors. This therapeutic approach significantly improved care patients with numerous immune‐related conditions; however, many are unresponsive, some develop adverse events. One reason for that lack consideration localization these surface in context synapse. In addition blocking binding, changing location within different compartments immunological synapse could serve as an alternative, efficient, safer treating patients. review discusses potential advantages altering proteins' summarizes published work field. It also novel use bispecific induce clustering surface. presents rationale developing antibodies, organization receptor complexes offers innovative emerging technology resistant current immunotherapies.

Language: Английский

Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade DOI
Kun Pang, Zhenduo Shi, Liuya Wei

et al.

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 66, P. 100907 - 100907

Published: Nov. 30, 2022

Language: Английский

Citations

134
Exploring Immune Checkpoint Inhibitors: Focus on PD-1/PD-L1 Axis and Beyond DOI
Durre Aden, Samreen Zaheer, Niti Sureka

et al.

Pathology - Research and Practice, Journal Year: 2025, Volume and Issue: 269, P. 155864 - 155864

Published: March 1, 2025

Language: Английский

Citations

5
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

16
Mitochondrial DNA-targeted therapy: A novel approach to combat cancer DOI Creative Commons

Yumeng Lin,

Bowen Yang, Yibo Huang

et al.

Cell Insight, Journal Year: 2023, Volume and Issue: 2(4), P. 100113 - 100113

Published: July 22, 2023

Mitochondrial DNA (mtDNA) encodes proteins and RNAs that are essential for mitochondrial function cellular homeostasis, participates in important processes of bioenergetics metabolism. Alterations mtDNA associated with various diseases, especially cancers, considered as biomarkers some types tumors. Moreover, alterations have been found to affect the proliferation, progression metastasis cancer cells, well their interactions immune system tumor microenvironment (TME). The role development makes it a significant target treatment. In recent years, many novel therapeutic methods targeting emerged. this study, we first discussed how cancerogenesis is triggered by mutations, including gene copy number, aberrant expression epigenetic modifications. Then, described detail mechanisms underlying between extramitochondrial environment, which crucial understanding efficacy safety mtDNA-targeted therapy. Next, provided comprehensive overview progress therapy strategies mtDNA. We classified them into two categories based on action: indirect direct strategies. Indirect aimed induce damage dysfunction modulating pathways involved stability integrity, while utilized molecules can selectively bind or cleave achieve efficacy. This study highlights importance treatment, will provide insights future research targeted drugs

Language: Английский

Citations

24
Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma DOI Creative Commons
Yi‐Wei Xu, Xiaodong Hao, Yidan Ren

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 12

Published: Jan. 6, 2023

Tumors meet their energy, biosynthesis, and redox demands through metabolic reprogramming. This abnormality results in elevated levels of metabolites, particularly lactate, the tumor microenvironment. Immune cell reprogramming cellular plasticity mediated by lactate lactylation increase immunosuppression microenvironment are emerging as key factors regulating development, metastasis, effectiveness immunotherapies such immune checkpoint inhibitors. Reprogramming glucose metabolism “Warburg effect” hepatocellular carcinoma (HCC) lead to massive production accumulation so modification tissue is likely be abnormal well. article reviews regulation therapeutic strategy targeting lactate-immunotherapy, which will help better guide medication treatment patients with carcinoma.

Language: Английский

Citations

23
Extracellular Vesicles as Delivery Shippers for Noncoding RNA‐Based Modulation of Angiogenesis: Insights from Ischemic Stroke and Cancer DOI
Yongli Pan, Yuheng Liu, Wei Wei

et al.

Small, Journal Year: 2023, Volume and Issue: 19(17)

Published: Jan. 2, 2023

Ischemic stroke and systemic cancer are two of the leading causes mortality. Hypoxia is a central pathophysiological component in ischemic cancer, representing joint medical function. This function includes angiogenesis regulation. Vascular remodeling coupled with axonal outgrowth following cerebral ischemia critical improving poststroke neurological functional recovery. Antiangiogenic strategies can inhibit vascularization play vital role impeding growth, invasion, metastasis. Although there significant differences cause across both conditions, emerging evidence states that common signaling structures, such as extracellular vesicles (EVs) noncoding RNAs (ncRNAs), involved this context. EVs, heterogeneous membrane encapsulating proteomic genetic information from parental cells, act multifunctional regulators intercellular communication. Among multifaceted roles modulating biological responses, exhaustive shows ncRNAs selectively sorted into specific aspects development prognosis, namely, angiogenesis. review will discuss recent advancements EV-facilitated/inhibited progression elements particular concern about within these vesicles. The concluded by underlining clinical opportunities EV-derived diagnostic, prognostic, therapeutic agents.

Language: Английский

Citations

17
PD-1 signaling uncovers a pathogenic subset of T cells in inflammatory arthritis DOI Creative Commons

Johanna Straube,

Shoiab Bukhari, Shalom Lerrer

et al.

Arthritis Research & Therapy, Journal Year: 2024, Volume and Issue: 26(1)

Published: Jan. 22, 2024

Abstract Background PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in cell activation enhanced response tumors pathogens. Reciprocally, despite a decade of research, approaches treat autoimmunity with agonists have only had limited successful. To resolve this, new methods must be developed augment function beyond engaging the receptor. Methods We conducted flow cytometry analysis cells isolated from peripheral blood synovial fluid patients rheumatoid arthritis. In addition, we performed genome-wide CRISPR/Cas9 screen identify genes associated signaling. further analyzed involved signaling using publicly available bulk single-cell RNA sequencing datasets. Results Our confirmed known regulators proximal and, importantly, identified additional 1112 unique related ability inhibit functions. These were strongly cancer blockades high tumor dysfunction exclusion scores, confirming their role downstream PD-1. Functional annotation revealed that most significant uncovered those regulation processes. Remarkably, these considerably downregulated inflammatory arthritis, supporting overall inhibitory A study arthritis data demonstrated five genes, KLRG1, CRTAM, SLAMF7, PTPN2, KLRD1, activated effector fluids. Backgating canonical cytotoxic signatures + HLA-DR HIGH KLRG1 LOW as novel subset cells. Conclusions concluded are potential target for future diseases. uncovers functions therefore, provides comprehensive resource studies much needed characterize

Language: Английский

Citations

6
Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening DOI Creative Commons

Azucena Ramos,

Catherine Koch,

Yunpeng Liu-Lupo

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 5, 2023

Abstract CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through variety of means, including loss cells antigen escape. To investigate leukemia-intrinsic resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model acute lymphoblastic leukemia (B-ALL) utilizing modular guide RNA library. We identified IFN γ R/JAK/STAT signaling components processing presentation pathway as key mediators to vivo ; intriguingly, this yielded the opposite effect vitro (sensitized cells). Transcriptional characterization demonstrated upregulation these pathways tumors relapsed after treatment, functional studies showed surprising role natural killer (NK) engaging program. Finally, examination data from B-ALL treated with revealed association between poor outcomes increased expression JAK/STAT MHC-I cells. Overall, our identify unexpected mechanism which tumor cell interaction microenvironment, NK cells, induces adaptive, therapy-induced, T-cell program

Language: Английский

Citations

11
Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors DOI

Zheng Jiamin,

Zhisen Zhang, Xiaoyu Ding

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 270, P. 116390 - 116390

Published: April 1, 2024

Language: Английский

Citations

4
De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression DOI Creative Commons
Naveen Kumar Tangudu, Raquel Buj, Hui Wang

et al.

Cancer Research Communications, Journal Year: 2024, Volume and Issue: 4(5), P. 1174 - 1188

Published: April 16, 2024

Abstract p16 is a tumor suppressor encoded by the CDKN2A gene whose expression lost in approximately 50% of all human cancers. In its canonical role, inhibits G1–S-phase cell cycle progression through suppression cyclin-dependent kinases. Interestingly, also has roles metabolic reprogramming, and we previously published that loss promotes nucleotide synthesis via pentose phosphate pathway. However, broader impact p16/CDKN2A on other pathways potential therapeutic targets remains unexplored. Using CRISPR knockout libraries isogenic mouse melanoma lines, determined several metabolism genes essential for survival cells with p16/CDKN2A. Consistently, many these are upregulated knockdown or endogenously low expression. We sensitive to multiple inhibitors de novo purine synthesis, including antifolates. Finally, tumors were more antifolate methotrexate vivo than control tumors. Together, our data provide evidence reevaluate utility drugs patients p16/CDKN2Alow as may window agents. Significance: Antimetabolites first chemotherapies, yet have failed clinic due toxicity poor patient selection. Our suggest provides kill cancer widely-used antifolates relatively little toxicity.

Language: Английский

Citations

4