Unraveling Heterogeneity of Tumor Cells and Microenvironment and Its Clinical Implications for Triple Negative Breast Cancer

Jiang, Ke; Dong, Mengting; Li, Chunyang; Sheng, Jiayu

doi:10.3389/fonc.2021.557477

Cited by 18 publications

(21 citation statements)

References 30 publications

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“…Macrophages are typically subclassed within the TIME as classically activated, anti-tumour M1-or alternatively activated, pro-tumour M2-like macrophages, also known as tumour associated macrophages (TAMs). Higher proportions of CD68 + macrophages are seen in TNBC compared to hormone-positive disease, with higher reported unpolarised M0-and M1-like subtype proportions [44][45][46] . However, further studies have shown that TNBC may selectively cause unpolarised macrophages to become TAMs, and thus other studies have shown TAMs to be in greater proportions 47,48 .…”

Section: Discussionmentioning

confidence: 97%

“…adjuvant or neoadjuvant) seems to have no effect on the prognostic significance, increasing the value macrophages may have as a clinical biomarker. Single cell RNA-sequencing has found smaller proportions of TAMs within the TIME of TNBC, however high expression of the M2 subtype is associated with poorer overall survival (p = 0.002) 46 . An analysis of metastatic TNBC found non-response to neoadjuvant nab-paclitaxel and pembrolizumab resulted in a lower CD68 signature with higher CSF1R-expressing TAMs 62 .…”

Section: Discussionmentioning

confidence: 99%

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Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer

Wang

Browne

Šlapetová

et al. 2021

Sci Rep

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Triple negative breast cancer (TNBC) comprises 10–15% of all breast cancers and has a poor prognosis with a high risk of recurrence within 5 years. PD-L1 is an important biomarker for patient selection for immunotherapy but its cellular expression and co-localization within the tumour immune microenvironment and associated prognostic value is not well defined. We aimed to characterise the phenotypes of immune cells expressing PD-L1 and determine their association with overall survival (OS) and breast cancer-specific survival (BCSS). Using tissue microarrays from a retrospective cohort of TNBC patients from St George Hospital, Sydney (n = 244), multiplexed immunofluorescence (mIF) was used to assess staining for CD3, CD8, CD20, CD68, PD-1, PD-L1, FOXP3 and pan-cytokeratin on the Vectra Polaris™ platform and analysed using QuPath. Cox multivariate analyses showed high CD68+PD-L1+ stromal cell counts were associated with improved prognosis for OS (HR 0.56, 95% CI 0.33–0.95, p = 0.030) and BCSS (HR 0.47, 95% CI 0.25–0.88, p = 0.018) in the whole cohort and in patients receiving chemotherapy, improving incrementally upon the predictive value of PD-L1+ alone for BCSS. These data suggest that CD68+PD-L1+ status can provide clinically useful prognostic information to identify sub-groups of patients with good or poor prognosis and guide treatment decisions in TNBC.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer

Wang

Browne

Šlapetová

et al. 2021

Sci Rep

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“…The tumor microenvironment (TME) has been identified playing a critical role in tumor heterogeneity, but the mechanism has not been fully elucidated. Emerging evidence demonstrated that the TME comprises endothelial cells, fibroblasts, immune cells, and extracellular components that contribute to tumor heterogeneity ( Jiang et al, 2021 ; Yuan et al, 2021 ). According to the characteristics of TME, BC was classified into different TME clusters ( Xiao et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in ER (+) and/or PR (+) and HER2 (−) Breast Cancer

Zheng

Han

et al. 2022

Front. Pharmacol.

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Background: Although intrinsic molecular subtype has been widely used, there remains great clinical heterogeneity of prognosis in the estrogen receptor (ER)- and/or progesterone receptor (PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC).Methods: The transcriptome expression data of messenger RNA (mRNA) were downloaded from The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and the Gene Expression Omnibus (GEO) databases. Immune-related genes were acquired from the ImmPort database and additional literature search. Univariate Cox, LASSO regression, and multivariate Cox regression were used to screen prognostic immune-related genes and establish the risk signature. The correlation between the risk signature and clinical characteristics, the abundances of immune cells within the tumor microenvironment, and cancer phenotypes were further assessed.Results: Of note, 102 immune-related prognostic genes were identified in the METABRIC dataset by univariate Cox analysis. Consecutively, 7 immune-related genes (SHMT2, AGA, COL17A1, FLT3, SLC7A2, ATP6AP1, and CCL19) were selected to establish the risk signature by LASSO regression and multivariate Cox analysis. Its performance was further verified in TCGA and GSE21653 datasets. Multivariate Cox analysis showed that the risk signature was an independent prognostic factor. The 7-gene signature showed a significant correlation with intrinsic molecular subtypes and 70-gene signature. Furthermore, the CD4+ memory T cells were significantly higher in the low-risk group while a significantly higher proportion of M0-type macrophages was found in the high-risk group in both METABRIC and TCGA cohorts, which may have an influence on the prognosis. Furthermore, we found that the low-risk group may be associated with the immune-related pathway and the high-risk group was with the cell cycle-related pathway, which also showed an impact on the prognosis.Conclusion: These seven immune-related gene risk signatures provided an effective method for prognostic stratification in ER (+) and/or PR (+) and HER2 (−) BC.

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“…Since intratumoral heterogeneity and the presence of phenotypically distinct tumor cells within a single tumor is critical to cancer progression and resistance to therapy, understanding the molecular mechanisms underlying the intratumor phenotypic heterogeneity is key for therapeutic targeting of TNBC [9].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Heterogeneity Drives Differential Disease Outcome in Triple Negative Breast Cancer

Thankamony¹,

Murali²,

Chakraborty³

et al. 2022

Preprint

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The triple-negative breast cancer (TNBC) subtype is one of the most aggressive forms of breast cancer that has poor clinical outcome and still remains as an unmet clinical challenge. Accumulating evidence suggests that intratumoral heterogeneity or the presence of phenotypically heterogeneous cell populations within a tumor plays a crucial role in chemoresistance, tumor progression and metastasis. Increased understanding of the molecular regulators of intratumoral heterogeneity will enable the development of effective therapeutic strategies in TNBC. We have identified a molecular mediator involved in intratumoral heterogeneity in breast cancer using an unbiased approach. We isolated two heterogeneous tumor cell populations from the 4T1 TNBC tumor model and phenotypic characterization revealed that the cells are distinct in terms of their morphology, proliferation and self-renewal ability in vitro; as well as primary tumor formation and metastatic potential in vivo. Further, RNA sequencing on both cell populations was performed to identify the molecular mediators underlying this heterogeneity. Bioinformatic analysis performed on the differentially expressed genes along with the Kaplan-Meier survival analysis in TNBC patients identified Metastasis associated colon cancer 1 (Macc1) as the top candidate gene mediating the aggressive phenotype. The role of Macc1 in regulating the proliferative phenotype was validated using siRNA mediated gene knockdown. The role of Macc1 in the aggressive cancer cell phenotypes and disease progression is being studied further using a small molecule transcriptional inhibitor of Macc1 in cell line and animal models, thus increasing our understanding of the molecular underpinnings of intratumoral heterogeneity in breast cancer that is critical to the improvement in the treatment of women currently living with the highly aggressive TNBC subtype.

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Unraveling Heterogeneity of Tumor Cells and Microenvironment and Its Clinical Implications for Triple Negative Breast Cancer

Cited by 18 publications

References 30 publications

Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer

Multiplexed immunofluorescence identifies high stromal CD68+PD-L1+ macrophages as a predictor of improved survival in triple negative breast cancer

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in ER (+) and/or PR (+) and HER2 (−) Breast Cancer

Phenotypic Heterogeneity Drives Differential Disease Outcome in Triple Negative Breast Cancer

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