S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy

Li, Jianjie; Shu, Xiaodong; Xu, Jun; Su, Sek Man; Chan, Un In; Mo, Li‐Hua; Liu, Jianlin; Zhang, Xin; Adhav, Ragini; Chen, Qiang; Wang, Yuqing; An, Tingting; Zhang, Xu; Lyu, Xueying; Li, Xiaoling; Lei, Josh Haipeng; Kai, Masahiro; Xing, Fuqiang; Zhang, Aiping; Deng, Chu‐Xia; Xu, Xiaoling

doi:10.1038/s41467-022-29151-5

Cited by 45 publications

(40 citation statements)

References 53 publications

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“…The S100A9-RAGE-NF-κB-JunB pathway in brain metastasis has been identified as a potential mediator of brain radiotherapy resistance in the organ (Monteiro et al, 2022). S100A9-CXCL12 signaling with an αPD-1 antibody could be effectively suppressed by the treatment of inhibitors for breast cancer (Li et al, 2022). S100A9 overexpression in obesity impaired macrophage differentiation via TLR4-NFkB signaling, worsening inflammation and wound healing (Franz et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Xin

Cao

et al. 2022

Front. Microbiol.

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BackgroundIdentifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention.MethodsBased on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis.ResultsTotally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57–0.89) and 0.69 (95% CI: 0.52–0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63–0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22–86.30%) and 55.63% (95% CI: 29.17–61.00%).ConclusionOur findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

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Section: Discussionmentioning

confidence: 99%

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Xin

Cao

et al. 2022

Front. Microbiol.

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“…We observed a trend when assessing sensitivity of the models by grade where low and intermediate grades of cancer had better sensitivities. The performance of the models for lower grade cancer is not surprising given the roles of S100A8 and S100A9 in recruitment of immune cells essentially prepping the tissue for tumor formation [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a short-term breast health measure as a supplement to screening mammography

et al. 2022

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Background There is a growing body of evidence to support tears as a non-traditional biological fluid in clinical laboratory testing. In addition to the simplicity of tear fluid processing, the ability to access key cancer biomarkers in high concentrations quickly and inexpensively is significantly enhanced. Tear fluid is a dynamic environment rich in both proteomic and genomic information, making it an ideal medium for exploring the potential for biological testing modalities. Methods All protocols involving human subjects were reviewed and approved by the University of Arkansas IRB committee (13-11-289) prior to sample collection. Study enrollment was open to women ages 18 and over from October 30, 2017-June 19, 2019 at The Breast Center, Fayetteville, AR and Bentonville, AR. Convenience sampling was used and samples were age/sex matched, with enrollment open to individuals at any point of the breast health continuum of care. Tear samples were collected using the Schirmer strip method from 847 women. Concentration of selected tear proteins were evaluated using standard sandwich ELISA techniques and the resulting data, combined with demographic and clinical covariates, was analyzed using logistic regression analysis to build a model for classification of samples. Results Logistic regression analysis produced three models, which were then evaluated on cases and controls at two diagnostic thresholds and resulted in sensitivity ranging from 52 to 90% and specificity from 31 to 79%. Sensitivity and specificity variation is dependent on the model being evaluated as well as the selected diagnostic threshold providing avenues for assay optimization. Conclusions and relevance The work presented here builds on previous studies focused on biomarker identification in tear samples. Here we show successful early classification of samples using two proteins and minimal clinical covariates.

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“…The regulation and improvement of the tumor immune microenvironment are widely recognized to play an important role in cancer therapy [34,35]. The PMN has been shown to consist of various mature and immature immune cells, such as bone marrow-derived hematopoietic progenitor cells, MDSCs, macrophages and neutrophils, which accumulate in the pre-metastatic microenvironment of organs different to the primary site before the arrival of cancer cells [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts

Huang

Hou

Tsai

et al. 2022

Preprint

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BackgroundImpairment of metabolism is strongly associated with the development of cancer. However, the role of metabolic reprogramming in the remodeling of pre-metastatic niche (PMN), a key step in metastasis, is still unknown. We aimed to investigate the metabolic alternation during lung PMN formation.MethodsWe assessed the transcriptomes and lipidomics of lung of MMTV-PyVT mice by microarray and liquid chromatography-tandem mass spectrometry before lung metastasis. The validation of gene or protein expressions was performed by real-time quantitative polymerase chain reaction, immunoblot and immunohistochemistry. The lung fibroblasts were isolated from mice and then co-cultured with breast cancer to identify the influence of cancer on the change of lung fibroblasts in PMN.ResultsWe demonstrated changes in the lipid profile and several lipid metabolism genes in the lungs of breast cancer-bearing MMTV-PyVT mice before cancer spread. The expression of ACACA (acetyl-CoA carboxylase α) was downregulated in the lung fibroblasts, which contributed to changes in acetylation of protein’s lysine residues and the synthesis of fatty acid. The downregulation of ACACA in lung fibroblasts triggered a senescent and inflammatory phenotypic shift of lung fibroblasts in both in vivo and in vitro models. The senescence-associated secretory phenotype of lung fibroblasts enabled the recruitment of immunosuppressive granulocytic myeloid-derived suppressor cells into the lungs through the production of CXCL1 in the lungs. Knock-in of ACACA prevented lung metastasis in the MMTV-PyVT mouse model, further supporting that ACACA was involved in the remodeling of the lung PMN.ConclusionsTaken together, these data revealed a mechanism by which ACACA downregulation directs the formation of an immunosuppressive lung PMN in breast cancer.

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S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy

Cited by 45 publications

References 53 publications

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Development and validation of a short-term breast health measure as a supplement to screening mammography

Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts

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