A cutting-edge immunomodulatory interlinkage between HOTAIR and MALAT1 in tumor-associated macrophages in breast cancer: A personalized immunotherapeutic approach

Abstract

Breast cancer (BC) is one of the most common cancers, accounting for 2.3 million cases worldwide. BC can be molecularly subclassified into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These molecular subtypes differ in their prognosis and treatment strategies; thus, understanding the tumor microenvironment (TME) of BC could lead to new potential treatment strategies. The TME hosts a population of cells that act as antitumorigenic such as tumor-associated eosinophils or pro-tumorigenic such as cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), monocytic-derived populations such as MDSCs, or most importantly “tumor-associated macrophages (TAMs),” which are derived from CD14+ monocytes. TAMs are reported to have the pro-inflammatory phenotype M1, which is found only in the very early stages of tumor and is not correlated with progression; however, the M2 phenotype is anti-inflammatory that is correlated with tumor progression and metastasis. The current study focused on controlling the anti-inflammatory activity in TAMs of hormonal, HER2+, and TNBC by epigenetic fine-tuning of two immunomodulatory proteins, namely, CD80 and mesothelin (MSLN), which are known to be overexpressed in BC with pro-tumorigenic activity. Long non-coding RNAs are crucial key players in tumor progression whether acting as oncogenic or tumor suppressors. We focused on the regulatory role of MALAT1 and HOTAIR lncRNAs and their role in controlling the tumorigenic activity of TAMs. This study observed the impact of manipulation of MALAT1 and HOTAIR on the expression of both CD80 and MSLN in TAMs of BC. Moreover, we analyzed the interlinkage between HOTAIR and MALAT1 as regulators to one another in TAMs of BC. The current study reported an upstream regulatory effect of HOTAIR on MALAT1. Moreover, our results showed a promising use of MALAT1 and HOTAIR in regulating oncogenic immune-modulatory proteins MSLN and CD80 in TAMs of HER2+ and TNBC. The downregulation of MALAT1 and HOTAIR resulted in the upregulation of CD80 and MSLN, which indicates that they might have a cell-specific activity in TAMs. These data shed light on novel key players affecting the anti-inflammatory activity of TAMs as a possible therapeutic target in HER2+ and TNBC.

The current advances of lncRNAs in breast cancer immunobiology research

“…In these TAMs, the MALAT1 and HOTAIR silencing promotes the upregulation of CD80 and MSLN and the downregulation of VEGF-A. Furthermore, this study showed a cytotoxicity decrease in CD8 + T cells against TNBC cells treated with anti-PD-L1 inhibitor and cultured under conditioned media derived from TAMs with MALAT1 and HOTAIR silencing, indicating the role of both lncRNAs as tumor-extrinsic negative modulators of the antitumoral immune response in BC ( 109 ) ( Figure 3 ).…”

Long noncoding RNA MALAT-1: A versatile regulator in cancer progression, metastasis, immunity, and therapeutic resistance

“…At the beginning of oncogenesis, TAMs take on an M1-like pro-inflammatory phenotype, triggering an immune response that prevents tumor development. In a recent research investigation, T. Amer and colleagues sought to epigenetically control two immune-modulating proteins, CD80 and mesothelin (MSLN), which are highly expressed in breast cancer and have pro-tumorigenic impacts [ 208 ], in order to modulate the anti-inflammatory properties of TAMs in various breast cancer subtypes (hormonal, HER2+, and TNBC). They concentrated on MALAT-1 and HOTAIR as two particular lncRNAs to comprehend their regulatory functions in regulating the tumorigenic activity of TAMs.…”

“…They concentrated on MALAT-1 and HOTAIR as two particular lncRNAs to comprehend their regulatory functions in regulating the tumorigenic activity of TAMs. The researchers investigated the influence of altering MALAT-1 and HOTAIR on the expression of CD80 and MSLN in BC TAMs [ 208 ]. Increased expression of CD80 and MSLN was accompanied by downregulation of MALAT-1 and HOTAIR, indicating that these lncRNAs may have cell-specific functions in TAMs [ 208 ].…”

“…The researchers investigated the influence of altering MALAT-1 and HOTAIR on the expression of CD80 and MSLN in BC TAMs [ 208 ]. Increased expression of CD80 and MSLN was accompanied by downregulation of MALAT-1 and HOTAIR, indicating that these lncRNAs may have cell-specific functions in TAMs [ 208 ]. This work suggests a tailored immunotherapeutic strategy to regulate TAM-mediated immune reactions in breast cancer subtypes by epigenetically adjusting the expression of CD80 and MSLN by modifying MALAT-1 and HOTAIR.…”

HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer

“…HOTAIR has been reported to be an upstream regulator of MALAT1, and promising results have been obtained from the use of MALAT1 and HOTAIR in regulating oncogenic immune-modulatory proteins CD80 and MSLN in tumor-associated macrophages (TAMs) [ 120 ]. This study also investigated the association between HOTAIR and MALAT1 as regulators, highlighting the regulatory role of MALAT1 and HOTAIR lncRNAs in controlling the tumorigenic activity of TAMs in BC and examining the impact of manipulating MALAT1 and HOTAIR on the expression of CD80 and MSLN in TAMs for HER2 + and TNBC BC.…”