Future of PD-1/PD-L1 axis modulation for the treatment of triple-negative breast cancer

Nakhjavani, Maryam; Shigdar, Sarah

doi:10.1016/j.phrs.2021.106019

Cited by 29 publications

(23 citation statements)

References 93 publications

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“…In recent years, several novel therapeutic strategies of TNBC have emerged, such as antibody–drug conjugate therapy (ADC) [ 28 ], immune cell therapy, and photodynamic therapy/photothermal therapy (PDT/PTT) [ 29 – 31 ]. Among them, PTT has been widely demonstrated as a prospective non-invasive therapeutic regimen for cancer.…”

Section: Introductionmentioning

confidence: 99%

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

et al. 2022

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Background Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. Methods Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. Results Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. Conclusion mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

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Section: Introductionmentioning

confidence: 99%

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

et al. 2022

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“…However, only a minority of TNBC patients achieve durable clinical bene ts from anti-PD-1/L1 treatments (12). Hence, identi cation of the most suitable subgroups of TNBC patients that can really bene t from immunotherapy is urgently required.…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoints expression patterns predict prognosis and immune microenvironment remodeling in triple-negative breast cancer

Zhang

Jin

Pan³

et al. 2022

Preprint

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Targeting immune checkpoint molecules holds great promise for triple-negative breast cancer (TNBC). However, the expression landscape of immune checkpoint genes (ICGs) in TNBC remains largely unknown. Herein, we systematically investigated the ICGs expression patterns in 422 TNBC samples. Molecular typings based on the ICGs expression profiled were identified and the associations between ICGs molecular typing and tumor immune characteristics, clinical significance, and response to immune checkpoint inhibitors (ICIs) were further explored. We identified two ICGs clusters and two ICGs-related gene clusters, which were were involved in different survival outcomes, biological roles and infiltration levels of immune cells. We also established and ICGs Riskscore quantification system to assess the ICGs expression patterns for individuals. TNBC patients with lower ICGs Riskscore were characterized by increased immune cell infiltration, favorable clinical outcome and high sensitivity to ICIs therapy. We also developed a nomogram model combining clinicopathological variables to predict OS in TNBC and the proposed nomogram presents good performance. Genomic features analysis revealed that high ICGs-related riskscore group presented an increased tumor mutation burden compared with the low ICGs-related riskscore group. Collectively, dissecting the ICGs expression patterns not only provides a new insight of subtype of TNBC but also deepens the understanding of ICGs in tumor immune microenvironment.

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“…With the hope of boosting the patient’s immune system to kill cancer, one strategy has been to use immunotherapy targeting PD-1/PD-L1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and the hedgehog (Hh) and neuropilin-2 (NRP-2) signaling pathway (reviewed in [ 2 ]). So far, the most studied immunotherapy target in TNBC belongs to a group of antibodies targeting PD-1 and PD-L1 [ 4 ]. A subgroup of TNBC patients overexpressing PD-L1 were studied in the IMpassion130 Trial.…”

Section: Introductionmentioning

confidence: 99%

“…PD-L1 also plays some roles in the proliferation of cancer cells by affecting the mitogen-activated protein kinase (MAPK) pathway [ 7 ]. Therefore, blocking PD-L1 has at least two different outputs: Activating the immune system to kill cancer and inhibiting the proliferation of cancer cells [ 4 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Blockers of PD-1/PD-L1 Interaction for the Immunotherapy of Triple-Negative Breast Cancer-Brain Metastasis

Nakhjavani

Shigdar

2022

Cancers

Self Cite

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The limited treatment options for triple-negative breast cancer with brain metastasis (TNBC-BM) have left the door of further drug development for these patients wide open. Although immunotherapy via monoclonal antibodies has shown some promising results in several cancers including TNBC, it cannot be considered the most effective treatment for brain metastasis. This is due to the protective role of the blood–brain barrier (BBB) which limits the entrance of most drugs, especially the bulky ones such as antibodies, to the brain. For a drug to traverse the BBB via passive diffusion, various physicochemical properties should be considered. Since natural medicine has been a key inspiration for the development of the majority of current medicines, in this paper, we review several naturally-derived molecules which have the potential for immunotherapy via blocking the interaction of programmed cell death protein-1 (PD-1) and its ligand, PD-L1. The mechanism of action, physicochemical properties and pharmacokinetics of these molecules and their theoretical potential to be used for the treatment of TNBC-BM are discussed.

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Future of PD-1/PD-L1 axis modulation for the treatment of triple-negative breast cancer

Cited by 29 publications

References 93 publications

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

Immune checkpoints expression patterns predict prognosis and immune microenvironment remodeling in triple-negative breast cancer

Natural Blockers of PD-1/PD-L1 Interaction for the Immunotherapy of Triple-Negative Breast Cancer-Brain Metastasis

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