Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment

Khaja, Azharuddin Sajid Syed; Toor, Salman M; Salhat, Haytham El; Faour, Issam; Haq, Navid Ul; Ali, Bassam R.; Elkord, Eyad

doi:10.18632/oncotarget.16565

Cited by 100 publications

(58 citation statements)

References 56 publications

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“…These data are supported by several studies, including an analysis of >100 treatment naïve BC patients where Treg abundance in the tumor microenvironment was characterized by high levels of surface CCR8, CTLA-4, and PD-1 ( 69 ). Another study similarly found that FOXP3 + Helios + CTLA-4 hi PD-1 hi CD4 + TIL characterize Tregs infiltrating BC ( 28 ). Overall, current findings indicate that dual checkpoint inhibition targeting CTLA-4 and PD-1 potentially has important synergistic effects due to their distinct regulatory activities ( 70 ).…”

Section: Discussionmentioning

confidence: 93%

“…No clinical significance has been attributed to expression of the alternate PD-1 ligand PD-L2 ( 27 ). The first immune checkpoint molecule targeted in the clinic, CTLA-4, was analyzed in BC with the presence of CTLA-4 + , PD-1 + , Helios + , FOXP3 + , GITR + , and/or CD103 + Tregs suggestive of an immunosuppressive microenvironment ( 28 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

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Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

et al. 2017

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There is an exponentially growing interest in targeting immune checkpoint molecules in breast cancer (BC), particularly in the triple-negative subtype where unmet treatment needs remain. This study was designed to analyze the expression, localization, and prognostic role of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM3 in primary BC. Gene expression analysis using the METABRIC microarray dataset found that all six immune checkpoint molecules are highly expressed in basal-like and HER2-enriched compared to the other BC molecular subtypes. Flow cytometric analysis of fresh tissue homogenates from untreated primary tumors show that PD-1 is principally expressed on CD4+ or CD8+ T cells and CTLA-4 is expressed on CD4+ T cells. The global proportion of PD-L1+, PD-L2+, LAG3+, and TIM3+ tumor-infiltrating lymphocytes (TIL) was low and detectable in only a small number of tumors. Immunohistochemically staining fixed tissues from the same tumors was employed to score TIL and tertiary lymphoid structures (TLS). PD-L1+, PD-L2+, LAG3+, and TIM3+ cells were detected in some TLS in a pattern that resembles secondary lymphoid organs. This observation suggests that TLS are important sites of immune activation and regulation, particularly in tumors with extensive baseline immune infiltration. Significantly improved overall survival was correlated with PD-1 expression in the HER2-enriched and PD-L1 or CTLA-4 expression in basal-like BC. PD-1 and CTLA-4 proteins were most frequently detected on TIL, which supports the correlations observed between their gene expression and improved long-term outcome in basal-like and HER2-enriched BC. PD-L1 expression by tumor or immune cells is uncommon in BC. Overall, the data presented here distinguish PD-1 as a marker of T cell activity in both the T and B cell areas of BC associated TLS. We found that immune checkpoint molecule expression parallels the extent of TIL and TLS, although there is a noteworthy amount of heterogeneity between tumors even within the same molecular subtype. These data indicate that assessing the levels of immune checkpoint molecule expression in an individual patient has important implications for the success of therapeutically targeting them in BC.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

et al. 2017

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“…In this study, we focused on the expression of multiple immune checkpoints in the peripheral blood of primary breast and colorectal cancer patients compared with healthy donors. Studies reported that expressions of multiple ICs including PD-1 and CTLA-4 were elevated in the circulation of both PBC 19,20 and CRC. 21 We have recently reported that the promoter demethylation and post-translational histone modifications play a role in the regulation of immune checkpoints in PBC and CRC tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

et al. 2018

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Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/ anti-TIGIT could be a more efficient therapeutic strategy in cancer patients. ARTICLE HISTORY

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“…The triple-negative BC (TNBC) subtype is the most aggressive subtype, and it is further classified into four subtypes: luminal/androgen receptor (LAR), mesenchymal (MES), basal-like immune suppressed (BLIS), and basal-like immune activated (BLIA) subtypes (4). The triplenegative subtype was demonstrated in several studies to frequently express the programmed cell death-ligand 1 (PD-L1) (5,6); there exist an overall immune system dysfunction and suppression throughout different BC subtypes due to the abundance of immune suppressive cells, namely, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), within the BC tumor microenvironment (7).…”

Section: Introductionmentioning

confidence: 99%

XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients

2020

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Escaping antitumor immunity is a hallmark in cancer progression. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor responsible for the maintenance of immune tolerance; PD-1 ligand (PD-L1) is overexpressed in tumor cells, simplifying their escape from the immune system through T-cell function suppression. Notwithstanding that cancer antigen (CA)125, carcinoembryonic antigen (CEA), CA15-3, and alpha-fetoprotein (AFP) are among conventional breast cancer diagnostic biomarkers, their lack of sensitivity and specificity resides among their major limitations. Furthermore, human epidermal growth factor receptor (HER)2 and interleukin (IL)-6-demonstrated as breast cancer immune biomarkers-still possess limitations, for instance, technical detection problems and stability problems, which necessitate the discovery of novel, stable non-invasive cancer immune biomarkers. XIST and TSIX are two long non-coding (lnc)RNAs possessing a role in X chromosome inactivation (XCI) as well as in breast cancer (BC). In the present study, they were investigated as stable non-invasive breast cancer immune biomarkers. The study demonstrated that PD-L1 was overexpressed in the different molecular subtypes of breast cancer patients as well as in MDA-MB-231 cells. Furthermore, lncRNAs XIST and TSIX were markedly increased in the tissues, lymph nodes, and different body fluids of breast cancer patients compared to controls. In addition, XIST and TSIX were differentially expressed in subtypes of BC patients, and their levels were correlated to PD-L1 expression level. In conclusion, this correlative study has shed light on the role of both lncRNAs XIST and TSIX as potential non-invasive BC immune biomarkers reflecting the evaded immune system of the patient and overcoming the instability problem of common BC biomarkers.

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Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment

Cited by 100 publications

References 56 publications

Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients

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