FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast

Lal, Aseem; Chan, Loretta; DeVries, Sandy; Chin, Koei; Scott, Gary K.; Benz, Christopher C.; Chen, Yunn Yi; Waldman, Frederic M.; Hwang, E. Shelley

doi:10.1007/s10549-013-2556-4

Cited by 57 publications

(37 citation statements)

References 28 publications

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“…Overall, higher numbers of Tregs were found in DCIS than in normal breast tissue, with the highest number found in invasive breast carcinoma (29). Similar findings were reported by Lal and colleagues (30). Interestingly, Treg infiltration in pancreatic cancer also appears to increase from normal tissue to preinvasive lesions to invasive adenocarcinoma (31).…”

Section: Discussionsupporting

confidence: 85%

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Hendry

Pang

Byrne

et al. 2017

Clinical Cancer Research

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Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n ¼ 55) and mutation data (n ¼ 20).Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%-90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P ¼ 0.002/0.035), ER-negative (P ¼ 0.02/0.02), and ERBB2-amplified tumors (P < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P ¼ 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P < 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210-7.Ó2017 AACR.

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Section: Discussionsupporting

confidence: 85%

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Hendry

Pang

Byrne

et al. 2017

Clinical Cancer Research

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“…Previous genomic characterization of DCIS cases have identified gene expression signatures implying the presence of activated T cells in a subset of tumors (36), but this was not confirmed by any other method. Prior studies have also shown that the frequencies of Tregs increased during tumor progression suggesting that this could be used to predict risk of invasive progression (13). However, in our experience the frequency of FOXP3 + T cells is very low in DCIS (<10% of T cells) and their topologic distribution is highly variable within tumors making their accurate assessment inaccurate in thin tissue sections (see Supplementary Methods).…”

Section: Discussionmentioning

confidence: 99%

Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition

et al. 2017

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To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS recurrent IDC. TCR clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT expressing T cells were more frequent in DCIS whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple negative IDCs. Co-amplification of 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show co-evolution of cancer cells and the immune microenvironment during tumor progression.

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“…Increased inflammation in DCIS is associated with high nuclear grade, HER2 positivity, and extent of lesions [30,31]. FoxP3+ Tregs have been identified in DCIS lesions, although they were not associated with grade [32]. Esserman and coworkers found that CD68 + macrophages were associated with large, pathologically dense, high-grade DCIS lesions with comedonecrosis [13].…”

Section: Introductionmentioning

confidence: 99%

Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast

Campbell

Baehner

O'Meara

et al. 2016

Breast Cancer Res Treat

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Purpose The recent increase in the incidence of ductal carcinoma in situ (DCIS) has sparked debate over the classification and treatment of this disease. Although DCIS is considered a precursor lesion to invasive breast cancer, some DCIS may have more or less risk than is realized. In this study, we characterized the immune microenvironment in DCIS to determine if immune infiltrates are predictive of recurrence. Methods Fifty-two cases of high-grade DCIS (HG-DCIS), enriched for large lesions and a history of recurrence, were age matched with 65 cases of non-high-grade DCIS (nHG-DCIS). Immune infiltrates were characterized by single- or dual-color staining of FFPE sections for the following antigens: CD4, CD8, CD20, FoxP3, CD68, CD115, Mac387, MRC1, HLA-DR, and PCNA. Nuance multispectral imaging software was used for image acquisition. Protocols for automated image analysis were developed using CellProfiler. Immune cell populations associated with risk of recurrence were identified using classification and regression tree analysis. Results HG-DCIS had significantly higher percentages of FoxP3+ cells, CD68+ and CD68+PCNA+ macrophages, HLA-DR+ cells, CD4+ T cells, CD20+ B cells, and total tumor infiltrating lymphocytes (TILs) compared to nHG-DCIS. A classification tree, generated from 16 immune cell populations and 8 clinical parameters, identified three immune cell populations associated with risk of recurrence: CD8+HLADR+ T cells, CD8+HLADR− T cells, and CD115+ cells. Conclusion These findings suggest that the tumor immune microenvironment is an important factor in identifying DCIS cases with the highest risk for recurrence and that manipulating the immune microenvironment may be an efficacious strategy to alter or prevent disease progression.

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FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast

Cited by 57 publications

References 28 publications

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition

Characterizing the immune microenvironment in high-risk ductal carcinoma in situ of the breast

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