Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer DOI Creative Commons

Xijiao Ren,

Zhuo Cheng,

Jinming He

et al.

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

Published: Nov. 2, 2023

Abstract Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates the targeted delivery glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels immunosuppressive TME enhance response. Poly β-amino ester (PAE)-modified CTLA-4-antagonizing aptamers (aptPD-L1 aptCTLA-4) synthesized co-assembled into supramolecular nanoassemblies carrying BAY-876. The acidic microenvironment causes PAE protonation triggers dissociation initiate aptamer release. selectively inhibits glycolysis deprive uridine diphosphate N-acetylglucosamine downregulate N-linked glycosylation, thus facilitating recognition aptPD-L1 anti-PD-L1 therapy. Meanwhile, treatment also elevates supply tumor-residing cells (Tregs) metabolically rewiring them an immunostimulatory state, cooperating with aptCTLA-4-mediated immune-checkpoint inhibition abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms in preclinical models female mice provides distinct approach immunotherapy clinics.

Language: Английский

D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1 DOI Creative Commons
Ruonan Zhang, Yajing Yang,

Wenjing Dong

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(8)

Published: Feb. 18, 2022

Significance PD-L1 is well known as an immune checkpoint molecule, which suppresses surveillance through binding to its receptor PD-1. Intracellular can also protect messenger RNAs of several DNA damage repair–related genes from degradation and enhance tumor resistance DNA-damaging therapy. Triple-negative breast cancer (TNBC) has the worst prognosis highest risk distant relapse in shows immunotherapy radiotherapy. In this study, we found that D-mannose promote significantly radiotherapy TNBC. Since TNBC treatment still a clinical challenge, our findings provide strategies therapeutic efficacy may have application.

Language: Английский

Citations

155
FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer DOI Creative Commons
Yun Huang, Hailiang Zhang, Zhi‐Ling Li

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 11, 2021

Abstract Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, mechanisms of glycosylation regulation and whether sugar moiety contributes immunosuppression are unclear. Here, we identify aberrant show that N-glycosylation at NXT motif sites responsible for its protein stability in TNBC tumors. The fucosyltransferase FUT8 catalyzes core fucosylation N-glycans maintain high expression. Knockdown rescues B7H3-mediated immunosuppressive function cells. Abnormal mediated by overexpression can be physiologically important clinically relevant TNBC. Notably, combination inhibitor 2F-Fuc anti-PDL1 results enhanced therapeutic efficacy B7H3-positive These findings suggest targeting FUT8-B7H3 axis might promising strategy improving anti-tumor responses

Language: Английский

Citations

120
Biomarkers for breast cancer immunotherapy: PD-L1, TILs, and beyond DOI
Alessandro Rizzo, Angela Dalia Ricci

Expert Opinion on Investigational Drugs, Journal Year: 2021, Volume and Issue: 31(6), P. 549 - 555

Published: Nov. 18, 2021

Immune checkpoint inhibitors (ICIs) have recently entered into the therapeutic scenario of metastatic breast cancer. However, only a proportion patients benefit from ICIs and immune-based combinations, so identification reliable predictors response remains an unmet need.We discuss potential to in cancer, including PD-L1 expression, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), several other biomarkers suggest future directions research this setting. A literature search was conducted October 2021 Pubmed/Medline, Cochrane library Scopus databases; addition, abstract international cancer meetings were reviewed.In terms immunotherapy TNBC patients, are being evaluated. Valuable data on predictive emerged, host-related factors, immune-related cells, protein genetic markers. Data supporting triple-negative setting not concordant, but there been some positive phase III trials IMpassion130 KEYNOTE-355. Phase II (neo)adjuvant supportive strategy. Further investigations warranted challenging area.

Language: Английский

Citations

117
Recent advances in targeted strategies for triple-negative breast cancer DOI Creative Commons
Shuangli Zhu, Yuze Wu, Bin Song

et al.

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Aug. 28, 2023

Triple-negative breast cancer (TNBC), a highly aggressive subtype of cancer, negatively expresses estrogen receptor, progesterone and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is main form treatment for patients with TNBC, effectiveness TNBC still limited. The search more effective therapies urgent. Multiple targeted therapeutic strategies have emerged according to specific molecules signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, Notch poly ADP-ribose polymerase antibody-drug conjugates. Moreover, immune checkpoint example, pembrolizumab, atezolizumab, durvalumab, are widely explored clinic. We summarize recent advances therapy immunotherapy aim serving as reference development individualized future.

Language: Английский

Citations

117
Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer DOI Open Access

Eva Kúdelová,

Marek Smolár, Veronika Holubeková

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 14937 - 14937

Published: Nov. 29, 2022

Heterogeneity of triple-negative breast cancer is well known at clinical, histopathological, and molecular levels. Genomic instability greater mutation rates, which may result in the creation neoantigens enhanced immunogenicity, are additional characteristics this type. Clinical outcome poor due to early age onset, high metastatic potential, increased likelihood distant recurrence. Consequently, efforts elucidate mechanisms development, progression, spread have been initiated improve treatment options outcomes for these patients. The extremely complex heterogeneous tumor immune microenvironment made up several cell types commonly possesses disorganized gene expression. Altered signaling pathways mainly associated with mutated genes including p53, PIK3CA, MAPK, positively correlated regulating response. Of note, particular immunity-associated could be used prognostic indexes assess most effective management. Recent findings highlight fact that long non-coding RNAs also play an important role shaping formation, can mediate evasion. Identification signatures, through use multi-omics approaches, effector drive stages carcinogenic process steps developing new strategies targeted prevention. Advances immunotherapy by remodeling host system eradicate cells great promise lead novel therapeutic strategies. Current research focused on combining checkpoint inhibition chemotherapy, PARP inhibitors, vaccines, or natural killer therapy. Targeted therapies response, eliminate resistance, overall patient survival. In future, evolving advancements should implemented personalized medicine state-of-art management

Language: Английский

Citations

71
Triple negative breast cancer: Immunogenicity, tumor microenvironment, and immunotherapy DOI Creative Commons

Sotiris Loizides,

Anastasia Constantinidou

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

Published: Jan. 12, 2023

Triple negative breast cancer (TNBC) is a biologically diverse subtype of characterized by genomic and transcriptional heterogeneity exhibiting aggressive clinical behaviour poor prognosis. In recent years, emphasis has been placed on the identification mechanisms underlying complex biological profile TNBC, aiming to tailor treatment strategies. High immunogenicity, specific immune activation signatures, higher expression immunosuppressive genes levels stromal Tumor Infiltrating Lymphocytes, constitute some key elements driven landscape associated with TNBC. The unprecedented response TNBC immunotherapy undoubtedly changed standard care in this disease both early metastatic setting. However, extent interplay between infiltration mutational signatures yet be fully unravelled. present review, we evidence immunogenicity tumour microenvironment influence progression current paradigms based immunotherapy.

Language: Английский

Citations

61
Neutrophil Camouflaged Stealth Nanovehicle for Photothermal‐Induced Tumor Immunotherapy by Triggering Pyroptosis DOI Creative Commons

Xuya Yu,

Guozheng Xing,

Shupei Sheng

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(15)

Published: March 26, 2023

Abstract The regulation of tumor immunosuppressive microenvironments via precise drug delivery is a promising strategy for preventing recurrence and metastasis. Inspired by the stealth strategy, stealthy nanovehicle based on neutrophil camouflage developed to achieve immunotherapy triggering pyroptosis. comprises anti‐CD11b‐ IR820‐conjugated bovine serum albumin nanoparticles loaded with decitabine. Camouflaged neutrophils, nanovehicles efficient hitchhiking owing biotropism neutrophils tumors. fluorescent signal molecule, IR820, acts as navigation monitor track nanovehicle. released decitabine upregulates gasdermin E, laser irradiation activates caspase‐3, thereby resulting in pyroptosis, which improves system's adaptive immune response. In triple‐negative breast cancer animal model, it regulates microenvironment effective induces long‐lasting strong memory prevent lung

Language: Английский

Citations

58
Immature natural killer cells promote progression of triple-negative breast cancer DOI
Gatha Thacker,

Samantha Henry,

Ajeya Nandi

et al.

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(686)

Published: March 8, 2023

Natural killer (NK) cells are cytotoxic lymphocytes that accumulate within the tumor microenvironment and generally considered to be antitumorigenic. Using single-cell RNA sequencing functional analysis of multiple triple-negative breast cancer (TNBC) basal samples, we observed a unique subcluster Socs3 high CD11b − CD27 immature NK were present only in TNBC samples. These tumor-infiltrating expressed reduced granzyme signature and, mice, responsible for activating stem through Wnt signaling. cell–mediated activation these subsequently enhanced progression whereas depletion or ligand secretion from by LGK-974 decreased progression. In addition, cell inhibition their function improved anti–programmed death 1 (PD-L1) antibody chemotherapy response mice with TNBC. Furthermore, samples patients non-TNBC revealed increased numbers CD56 bright tumors correlated poor overall survival Together, our findings identify population protumorigenic may exploited both diagnostic therapeutic strategies improve outcomes

Language: Английский

Citations

44
Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy DOI Creative Commons
Zhilin Li, Qianfeng Zhang, Zhiqian Li

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(5), P. 2194 - 2209

Published: March 2, 2024

Despite the great potential of anti-PD-L1 antibodies for immunotherapy, their low response rate due to an immunosuppressive tumor microenvironment has hampered application. To address this issue, we constructed a cell membrane-coated nanosystem (mB4S) reverse immuno-supportive one strengthening anti-tumor effect. In system, Epirubicin (EPI) as immunogenic death (ICD) inducer was coupled branched glycopolymer

Language: Английский

Citations

30
Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts DOI

Ziwen Qiu,

Yingtao Zhong, Zhen‐Ming Lu

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(13), P. 9713 - 9735

Published: March 20, 2024

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve immunotherapy for fibrotic BRCA. FPC@S combines tumor ECM-targeting peptide, photosensitizer (protoporphyrin IX) an antifibrotic drug (SIS3). After anchoring causes ECM remodeling BRCA cell death generating reactive oxygen species (ROS) situ. Interestingly, ROS-mediated can normalize blood vessel hypoxia turn facilitate more ROS production. Besides, upon acidic microenvironment, will release SIS3 reprograming CAFs reduce their activity but not kill them, thus inhibiting fibrosis while preventing metastasis. The natural physical barrier formed dense is consequently eliminated BRCA, allowing drugs cells penetrate deep into tumors have better efficacy. Furthermore, stimulate system effectively suppress primary, distant metastatic combining with checkpoint blockade therapy. This study provides different insights development targeted delivery systems exploration synergistic immunotherapeutic mechanisms against aggressive

Language: Английский

Citations

27