B7 Family: History
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Subjects: Biology
Contributor:
Noora Karim Ahangar

B7 family members, as immune checkpoint molecules, can substantially regulate immune responses. Since microRNAs (miRs) can regulate gene expression post-transcriptionally, we conducted a scoping review to summarize and discuss the regulatory cross-talk between miRs and new B7 family immune checkpoint molecules, i.e., B7-H3, B7-H4, B7-H5, butyrophilin like 2 (BTNL2), B7-H6, B7-H7, and immunoglobulin like domain containing receptor 2 (ILDR2).

  • B7
  • microRNA
  • human diseases
  • cancer
  • immune checkpoint
  • immunotherapy
  • gene therapy

1. Introduction

Immune checkpoints can considerably regulate immune responses [1]. These molecules are critical for maintaining self-tolerance and preventing the stimulation of immune responses against normal peripheral tissues. Indeed, suppressing inhibitory axes, e.g., the immune checkpoint axis of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), has revolutionized cancer immunotherapy [2].

The B7 family is a group of immune checkpoints commonly expressed in different immune cells, such as antigen-presenting cells, T cells, B cells, natural killer cells, and various tissues. They play a crucial role in immune response; for example, they have substantial roles in directing the fate of T cells by binding their receptors. Various members of the B7 family have been identified, e.g., B7.1 (CD80), B7.2 (CD86), B7-H1 (PD-L1, or CD274), B7-DC (PD-L2, PDC1LG2, or CD273), B7-H2 (ICOSL: inducible T-cell co-stimulator ligand, or CD275), B7-H3 (CD276), B7-H4 (VTCN1), B7-H5 (VISTA: V-domain Ig suppressor of T cell activation, Dies1: differentiation of embryonic stem cells 1, or C10orf54), butyrophilin like 2 (BTNL2), B7-H6 (NCR3LG1: natural killer cell cytotoxicity receptor 3 ligand 1), B7-H7 (HHLA2: human endogenous retro virus–H long repeat-associating 2), and immunoglobulin like domain containing receptor 2 (ILDR2) [2][3][4][5][6]. Indeed, BTNL2 and ILDR2 are introduced as B7-like molecules, and further investigation is needed. B7 family genes have been linked with various pathological conditions, e.g., cancers, infections, autoimmune diseases, and transplantation complications [6]. Thus, a better understanding of their biology might pave the way for introducing novel strategies to treat the abovementioned diseases and complications.

MicroRNAs (miRs), as small, non-coding RNAs, can bind to their complementary sequences, which are often the mRNA 3′-untranslated regions (3′UTR) of their targets. Since miRs can cleave their target mRNAs by guiding the RNA-induced silencing complex (RISC) to target mRNAs, in order to direct the cleavage of mRNA through Argonaute (AGO) endonuclease activity [7], destabilize their target mRNAs via cutting their poly(A) tail, and make the translation of their target mRNA less effective, they are considered potent post-transcriptional gene regulators [8][9][10]. In higher eukaryotes, miRs can regulate the expression of approximately 60% of genes. It is well-established that miRs can contribute to many biological processes, e.g., cell growth, differentiation, metabolism, and immune response regulation [11][12]. Indeed, miRs can modulate the function of immune cells and regulate the expression of immune checkpoints [13][14][15]. Thus, alteration in miR expression is involved in the pathogenesis of various human diseases, like cancers [11][13][16]. Moreover, miRs can regulate the expression of B7 family members in various diseases; thus, there is a need to properly understand the scope and effect of this regulation in human diseases [17][18].

2. The Regulatory Cross-Talk between microRNAs and Novel Members of the B7 Family in Human Diseases

2.1. B7-H3

B7–H3, also referred to as CD276, can regulate the stimulation and inhibition of T cells [19][20]. A variety of cells, e.g., natural killer cells, activated T-cells, dendritic cells, macrophages, and non-hematopoietic cells, can express B7-H3 [21]. Preliminary findings reported that B7-H3 could promote CD4+ and CD8+ T cell proliferation by T cell receptor (TCR) stimulation using immobilized Ig fusion protein [19]. However, it is well-established that B7–H3 can suppress the activation of CD4+ T-cell and the release of effector cytokines [22][23]. This suppression might facilitate the function of transcription factors like nuclear factor of activated T cells (NF-AT), nuclear factor kappa B (NF-κB), and activator protein 1 (AP-1), playing significant roles in T cell function [22]. Moreover, B7-H3 overexpression has been identified in various cancers, e.g., breast [24], lung [25], kidney, prostate [26], and ovarian cancer [27]. Furthermore, the inhibition of B7-H3 has decreased angiogenesis in medulloblastoma, indicating its essential role in tumor angiogenesis [28]. As an overexpressed oncogene in various cancers, MYC has a critical role in cancer development, e.g., angiogenesis, apoptosis, proliferation [29][30]. Since MYC inhibition has been associated with the suppressed expression of B7-H3 in medulloblastoma cells, the MYC-B7-H3 regulatory axis can play an essential role in regulating angiogenesis [28]. It has been indicated that B7-H3 knockdown can repress the PI3K/Akt pathway, resulting in decreased STAT3 activity. Since STAT3 can promote the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), B7-H3 can regulate the expression of MMP2 and MMP9 [31]. Moreover, B7-H3 can be involved in inflammatory conditions, e.g., sepsis and bacterial meningitis [32]. Since the mRNA expression of B7–H3 is not as remarkable as its protein expression, the post-transcriptional regulating process might have a considerable effect [21].

2.2. B7-H4

B7-H4, also known as B7x, B7S1, and VTCN1, can inhibit cytokine production, proliferation, cell cycle progression, and the stimulation of CD4+ and CD8+ T cells [33][34]. Although its transcripts can be found in various tissues, its protein has low expression in most human normal tissues [35]. B7-H4 expression is positively correlated with cancer development in patients with gastric cancer [36], glioma [37], squamous cell esophageal carcinoma [38], renal cell carcinoma [39], pancreatic cancer [40], cholangiocarcinoma [18], ovarian cancer [41], and lung cancer [42]. Since B7-H4 has been associated with cancer development, it can be an appealing target for treating cancer patients [35].

It has been shown that miR-125b-5p has an anti-inflammatory role and can regulate interleukin (IL)-1β-induced inflammatory genes by targeting the TNF receptor associated factor (TRAF6)/mitogen-activated protein kinase (MAPK)/NF-κB pathway in human osteoarthritic chondrocytes [43]. However, miR-125b-5p overexpression in macrophages can increase IL-2 secretion and the proliferation of CD8+ T cells. Indeed, miR-125b-5p can target B7-H4 and facilitate inflammation [44]. In line with this, B7-H4 overexpression has been associated with poor prognosis in colorectal cancer patients [45]. In 24.4% of colorectal cancer patients, single-nucleotide polymorphism (SNP) rs13505 GG of B7-H4 can confer an alternate binding site for miR-1207–5p, which might result in downregulation of this gene [46]. Furthermore, TGF-β1 can upregulate B7-H4 and facilitate immune escape via the miR-155/miR-143 axis in colorectal cancer [47].

In 2017, 62 hsa-miRs were identified as regulating B7-H4 in pancreatic cancer [48]. These miRs were mentioned above in the Results section.

2.3. B7-H5

B7-H5, also known as VISTA, C10orf54, Dies1, and PD-1H, is a type-I membrane protein that can stimulate terminal differentiation of embryonic stem cells (ESCs) into cardiomyocytes/neurons via the bone morphogenetic protein (BMP) signaling pathway [49]. It has been reported that miR-125a-5p can directly repress the transcription of B7-H5 and inhibit ESC differentiation [50]. B7-H5 also plays a pivotal regulatory function in adipocyte differentiation independently from BMP signaling. In particular, the elevated level of B7-H5 has been shown exclusively in differentiated fat cells and blocked adipocyte differentiation [51]. In B7-H5 knockout mice, the elevation of inflammatory cytokines can result in chronic multi-organ inflammation, indicating the critical role of B7-H5 in suppressing inflammation [52]. In Crohn’s disease, there is a negative association between B7-H5 expression and hsa-miR-16–1 [53]. B7-H5 can serve as a ligand and receptor on T cells, suppressing the activation of naïve and memory T cells [54][55]. The presence of two PKC binding sites in the cytoplasmic region of B7-H5 might indicate that B7-H5 is a receptor [56][57]. B7-H5 can be overexpressed in cancer-associated/cancer-adjacent gastric myofibroblasts. However, B7-H5 expression is generally downregulated in epithelial gastric cancer cells. This can be explained by B7-H5 promoter methylation, the overexpression of miR-125a-5p, or a combination of both, and even the existence of mutant p53 [58]. Indeed, the downregulation of B7-H5 has been associated with de-differentiation and triggered epithelial–mesenchymal transition (EMT) in epithelial cells.

2.4. B7-H6

B7-H6, also known as NCR3LG1, is a ligand for the NKp30 [59]. B7-H6 sequence is functionally similar to the other B7 family members. Although B7-H6 is not found in normal human tissues, it is highly expressed in cancers, e.g., renal cell carcinoma, leukemia, breast cancer, ovarian cancer, and sarcomas [60]. Various factors can regulate B7-H6 expressions, e.g., protease inhibitors, proinflammatory cytokines, natural killer cells, and miRs. Histone deacetylase inhibitors (HDACi) and metalloprotease inhibitors can regulate the B7-H6 expression at transcription and post-transcriptional levels, respectively [61]. Following stimulation of CD14+CD16+ neutrophils and monocytes, B7-H6 can be expressed on these proinflammatory immune cells [62]. Tumoral B7-H6 can be recognized and eliminated via natural killer cells. However, metalloproteases can cleave B7-H6 and shield tumor cells from natural killer-mediated immune responses [63]. Bioinformatics analysis has predicted that miR-93, miR-195, and miR-340 can regulate immune responses by targeting B7-H6 in breast cancer cells [64].

2.5. B7-H7

B7-H7, which has previously been referred to as B7-H5, is known as the human endogenous retro virus–H long repeat-associating 2 (HHLA2) [65][66]. Its receptors can be found on various immune cells, e.g., monocytes, T cells, B cells, and dendritic cells. TMIGD2, which is referred to as CD28 homolog, is one of the identified B7-H7 receptors [67]. In antigen-presenting cells, B7-H7 co-stimulates the proliferation of naïve T cell and cytokine production across TMIGD2 by serine–threonine kinase AKT phosphorylation. However, the second B7-H7 receptor on activated T cells can exert a coinhibitory role, because activated T cells do not express TMIGD2. The identification of the second receptor might clarify the role of B7-H7 in T cell activation and the tumor microenvironment [68]. It has been reported that B7-H7 is upregulated in lung cancer, osteosarcoma, and breast cancer, and its elevated expression is correlated with a poor prognosis in affected patients [69]. BATF in B lymphocytes and SMAD in monocytes might be involved in the dysregulation of B7-H7 in kidney clear-cell carcinoma. It has been indicated that hsa-miR-6870–5p and hsa-miR-3116 might have a role in this modulatory mechanism [70].

2.6. Bioinformatics Analysis

Based on our results, four potential new interactions between B7 family members and miRs have been identified: (1) the hsa-miR-29b-3p/B7-H3 axis, (2) the hsa-miR-29a-3p/B7-H3 axis, (3) the hsa-miR-125a-5p/B7-H4 axis, and (4) the hsa-miR-486-5p/B7-H4 axis. Of these four interactions, the association of different isoforms of miR-29 with B7-H3 has been investigated in previous studies (see above). As mentioned earlier, hsa-miR-125a-5p regulates B7-H5 expression in gastric cancer, but its association with B7-H4 has not been studied. Recent findings have shown that miR-125a-5p plays a pivotal role in suppressing the classical activation of macrophages (M1-type) induced by lipopolysaccharide (LPS) stimulation, while promoting IL-4-induced expression of the alternative M2 macrophages by targeting KLF13, a transcriptional factor that is involved in T lymphocyte activation and inflammation [71]. In addition, miR-486-5p is an immunomodulatory tumor suppressor miR that has been reported to have key roles in various oncological and non-oncological disorders [72]. Although our knowledge about the role of miR-125a-5p/B7-H4 and miR-486-5p/B7-H4 axes in the immune pathways and the pathogenesis of various diseases is still preliminary, our in silico analysis can pave the way for further investigations.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22052652

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