PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity

Du, Ruoxin; Zhang, Xiangmei; Lu, Xiyan; Ma, Xiangmin; Guo, Xinyan; Shi, Chao; Xiaofei, REN; Ma, Xindi; He, Yutong; Gao, Yuan; Liu, Yunjiang

doi:10.1016/j.drup.2023.100947

Cited by 22 publications

(14 citation statements)

References 33 publications

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“…PDPN plays crucial functions in lymphangiogenesis ( Astarita, Acton & Turley, 2012 ; Renart et al, 2015 ), cancer invasiveness, extracellular matrix (ECM) remodeling ( Hoshino et al, 2011 ; Ito et al, 2012 ) as well as promoting an immunosuppressive microenvironment ( Sakai et al, 2018 ). For breast cancer, PDPN + -CAFs tended to result in a more malignant pathological status and could facilitate immunosuppression and disease progression, which is consistent with the finding of this meta-analysis study and the findings of PDPN functions in multiple types of solid tumors ( Du et al, 2023 ; Yamaguchi et al, 2021 ). Furthermore, recent research by Du et al (2023) suggests that PDPN + -CAFs contribute to HER-2-positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity.…”

Section: Discussionsupporting

confidence: 90%

The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: a systematic review and meta-analysis

Cui,

Dong,

Duan

et al. 2024

PeerJ

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Background To elucidate the relationship between cancer-associated fibroblast (CAFs) biomarkers and the prognosis of breast cancer patients for individualized CAFs-targeting treatment. Methodology PubMed, Web of Science, Cochrane, and Embase databases were searched for CAFs-related studies of breast cancer patients from their inception to September, 2023. Meta-analysis was performed using R 4.2.2 software. Sensitivity analyses were performed to explore the sources of heterogeneity. Funnel plot and Egger’s test were used to assess the publication bias. Results Twenty-seven studies including 6,830 patients were selected. Univariate analysis showed that high expression of platelet-derived growth factor receptor-β (PDGFR-β) (P = 0.0055), tissue inhibitor of metalloproteinase-2 (TIMP-2) (P < 0.0001), matrix metalloproteinase (MMP) 9 (P < 0.0001), MMP 11 (P < 0.0001) and MMP 13 (P = 0.0009) in CAFs were correlated with reduced recurrence-free survival (RFS)/disease-free survival (DFS)/metastasis-free survival (MFS)/event-free survival (EFS) respectively. Multivariate analysis showed that high expression of α-smooth muscle actin (α-SMA) (P = 0.0002), podoplanin (PDPN) (P = 0.0008), and PDGFR-β (P = 0.0470) in CAFs was associated with reduced RFS/DFS/MFS/EFS respectively. Furthermore, PDPN and PDGFR-β expression in CAFs of poorly differentiated breast cancer patients were higher than that of patients with relatively better differentiated breast cancer. In addition, there is a positive correlation between the expression of PDPN and human epidermal growth factor receptor-2 (HER-2). Conclusions The high expression of α-SMA, PDPN, PDGFR-β in CAFs leads to worse clinical outcomes in breast cancer, indicating their roles as prognostic biomarkers and potential therapeutic targets.

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Section: Discussionsupporting

confidence: 90%

The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: a systematic review and meta-analysis

Cui,

Dong,

Duan

et al. 2024

PeerJ

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“…Most inhibitors bind to IDO enzymes and prevent the conversion of tryptophan to kynurenine, resulting in toxic effects on NK cells and other immune substrates. The use of IDO/TDO-IN-2, a dual inhibitor targeting IDO3 and TDO1, reversed the inhibition of NK cell-mediated antibody-dependent cytotoxicity (ADCC) by oncolytic-positive cancer-associated fibroblasts and helped to attenuate Trastuzumab resistance in HER2 positive breast cancer [ 106 ]. In a study on sarcoma, an IDO inhibitor (GDC-0919) was in use.…”

Section: Strategies For Targeting Immunometabolism To Optimize Nk Cel...mentioning

confidence: 99%

Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy

Miao,

Lu,

Zhang

et al. 2024

J Transl Med

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Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.

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“…CAFs also generate matrixcrosslinking enzymes to mediated ECM remodeling, thereby increasing tumor stiffness (7). In addition, CAFs also secrete multiple growth factors, cytokines and exosomes which promote tumor growth and modulate therapy responses (8)(9)(10)(11). These CAF-derived factors can also act on a range of immune cells to cause immunosuppressive and immunopromoting consequences (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

scRNA-seq characterizing the heterogeneity of fibroblasts in breast cancer reveals a novel subtype SFRP4+ CAF that inhibits migration and predicts prognosis

Ning,

Quan,

Wang

et al. 2024

Front. Oncol.

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IntroductionCancer-associated fibroblasts (CAFs) are a diverse group of cells that significantly impact the tumor microenvironment and therapeutic responses in breast cancer (BC). Despite their importance, the comprehensive profile of CAFs in BC remains to be fully elucidated.MethodsTo address this gap, we utilized single-cell RNA sequencing (scRNA-seq) to delineate the CAF landscape within 14 BC normal-tumor paired samples. We further corroborated our findings by analyzing several public datasets, thereby validating the newly identified CAF subtype. Additionally, we conducted coculture experiments with BC cells to assess the functional implications of this CAF subtype.ResultsOur scRNA-seq analysis unveiled eight distinct CAF subtypes across five tumor and six adjacent normal tissue samples. Notably, we discovered a novel subtype, designated as SFRP4+ CAFs, which was predominantly observed in normal tissues. The presence of SFRP4+ CAFs was substantiated by two independent scRNA-seq datasets and a spatial transcriptomics dataset. Functionally, SFRP4+ CAFs were found to impede BC cell migration and the epithelial-mesenchymal transition (EMT) process by secreting SFRP4, thereby modulating the WNT signaling pathway. Furthermore, we established that elevated expression levels of SFRP4+ CAF markers correlate with improved survival outcomes in BC patients, yet paradoxically, they predict a diminished response to neoadjuvant chemotherapy in cases of triple-negative breast cancer.ConclusionThis investigation sheds light on the heterogeneity of CAFs in BC and introduces a novel SFRP4+ CAF subtype that hinders BC cell migration. This discovery holds promise as a potential biomarker for refined prognostic assessment and therapeutic intervention in BC.

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PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity

Cited by 22 publications

References 33 publications

The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: a systematic review and meta-analysis

The relationship between cancer associated fibroblasts biomarkers and prognosis of breast cancer: a systematic review and meta-analysis

Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy

scRNA-seq characterizing the heterogeneity of fibroblasts in breast cancer reveals a novel subtype SFRP4+ CAF that inhibits migration and predicts prognosis

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