Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Li, Feifei; Liu, Sheng

doi:10.3389/fimmu.2022.1083462

Cited by 15 publications

(12 citation statements)

References 124 publications

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“…It has been demonstrated that T-DM1 treatment increases tumor infiltrating NK cells that are responsible for trastuzumab-induced ADCC 55,56 in the absence or presence of immunotherapy 30 . Interestingly, we did not observe a significant change in the infiltration of NK cells upon T-DM1 treatment or upon treatment with the combination of T-DM1 and TACC3 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

Gedik,

Saatci,

Oberholtzer

et al. 2023

Preprint

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Immunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Targeting Tacc3 Induces Icd Leads To Immune Cell Infiltratio...mentioning

confidence: 99%

Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

Gedik,

Saatci,

Oberholtzer

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Another study revealed a decline in the levels of NKp46, a lysis receptor responsible for direct tumor cell elimination, within the TME compared to normal cells ( 199 ). Immunotherapies targeting NK cells encompass various strategies to improve their activity, including promoting ADCC with mABs ( 200 ), blocking inhibitory signals ( 201 ), utilizing cytokines to augment NK cell proliferation and cytotoxicity through CAR NKs ( 202 ), IL-15 ( 203 ), and adoptive transfer of NK cells ( 204 ). In recent years, adoptive cell therapy strategies have emerged as a promising approach for utilizing NK cells ( 205 ).…”

Section: Breast Tmementioning

confidence: 99%

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics

Akinsipe,

Mohamedelhassan,

Akinpelu

et al. 2024

Front. Immunol.

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The breast cancer tumor microenvironment (TME) is dynamic, with various immune and non-immune cells interacting to regulate tumor progression and anti-tumor immunity. It is now evident that the cells within the TME significantly contribute to breast cancer progression and resistance to various conventional and newly developed anti-tumor therapies. Both immune and non-immune cells in the TME play critical roles in tumor onset, uncontrolled proliferation, metastasis, immune evasion, and resistance to anti-tumor therapies. Consequently, molecular and cellular components of breast TME have emerged as promising therapeutic targets for developing novel treatments. The breast TME primarily comprises cancer cells, stromal cells, vasculature, and infiltrating immune cells. Currently, numerous clinical trials targeting specific TME components of breast cancer are underway. However, the complexity of the TME and its impact on the evasion of anti-tumor immunity necessitate further research to develop novel and improved breast cancer therapies. The multifaceted nature of breast TME cells arises from their phenotypic and functional plasticity, which endows them with both pro and anti-tumor roles during tumor progression. In this review, we discuss current understanding and recent advances in the pro and anti-tumoral functions of TME cells and their implications for developing safe and effective therapies to control breast cancer progress.

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“…Of note, ligands for NKG2D and DNAM-1 are poorly expressed in normal cells [proteinatlas.org, Genotype-Tissue Expression (GTEx) from The Cancer Genome Atlas (TCGA) database and (4)] and highly expressed in virus-infected and transformed cells (5,6). Furthermore, NK cells, through the expression of FcgRIIIA (CD16) receptor, are responsible for the antibody-dependent cellular cytotoxicity (ADCC) (7), which is a crucial function in the clinical context of all immunotherapies involving monoclonal antibodies (mAb) (8).…”

Section: Introductionmentioning

confidence: 99%

DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy

et al. 2023

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DNAM-1 is a major NK cell activating receptor and, together with NKG2D and NCRs, by binding specific ligands, strongly contributes to mediating the killing of tumor or virus-infected cells. DNAM-1 specifically recognizes PVR and Nectin-2 ligands that are expressed on some virus-infected cells and on a broad spectrum of tumor cells of both hematological and solid malignancies. So far, while NK cells engineered for different antigen chimeric receptors (CARs) or chimeric NKG2D receptor have been extensively tested in preclinical and clinical studies, the use of DNAM-1 chimeric receptor-engineered NK cells has been proposed only in our recent proof-of-concept study and deserves further development. The aim of this perspective study is to describe the rationale for using this novel tool as a new anti-cancer immunotherapy.

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Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Cited by 15 publications

References 124 publications

Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics

DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy

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