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Immune Checkpoint Gene Regulation by microRNA in Cancer
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Currently, the search for new promising tools of immunotherapy continues. In this regard, microRNAs that influence immune checkpoint gene expression in tumor and T-cells. An important feature of miRNA is its ability to affect the expression of several genes simultaneously, which corresponds to the trend toward the use of combination therapy. MiRNAs regulate gene expression by blocking mRNA translation. An important feature of miRNA is its ability to affect the expression of several genes simultaneously, which corresponds to the trend toward the use of combination therapy.

microRNA immune checkpoint immunotherapy
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Subjects: Oncology
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Update Date: 26 Aug 2022
Table of Contents

    1. Introduction

    Immunotherapy is an innovative method of cancer treatment. As a result of experiments and clinical trials, it has been found that immunotherapy can increase progressionfree survival and overall survival. However, this method of treatment is effective in a limited number of patients, and in addition, it can cause severe adverse reactions due to hyperreactivity of the immune system [1]. In this regard, research is underway to develop new therapeutic approaches based on targeting immune checkpoints (ICs). Tumor cells have the ability to generate ligands that can bind to co-inhibitory receptor molecules. This interaction suppresses the antitumor immune response, allowing the tumor to “escape” from the immune system. In order to increase the effectiveness of immunotherapy, the FDA approved a number of regimens, including a combination of two IC inhibitors, a combination of IC inhibitors and targeted therapy drugs, as well as antitumor bispecific antibodies [2][3]. It has been shown that in combination therapy regimens, patients experienced a higher response rate compared to monotherapy [4]. In addition, the search for a more promising immunotherapy approach is currently ongoing. In this regard, microRNAs (miRNAs) are considered. According to recent studies, miRNAs influence IC gene expression and are important regulators in both T-cells and tumor cells [5]. MiRNAs regulate gene expression by binding to the 3’-UTR of their mRNA [6][7][8]. MiRNAs can also affect IC expression indirectly, through molecules of different signaling pathways, such as PTEN, IFR-1, and others [9]. It is also important that one miRNA can affect several genes [5][10]. Here presents a entry of miRNAs that interact with IC genes, analyzes their regulating IC expression in tumors of various types of cancer, and identifies miRNAs that act on several IC genes simultaneously. Due to these properties, miRNA-based therapy may become an alternative to the combination of targeted drugs in the future. In addition, miRNAs are considered that are capable of simultaneously regulating the expression of targeted therapy genes along with IC genes. These issues have not been previously analyzed in existing reviews of miRNAs as IC regulators [11][12][13][14][15]. The researchers have reviewed more than 200 miRNAs that regulate ICs in tumors of various types.

    Table 1. The miRNAs interacting with IC genes in different types of cancer.

    Immune
    Checkpoint
    microRNA Cancer Reference
    PD-1 miR-374b, miR-4717 Liver cancer [16][17]
    PD-1/PD-L1 miR-183 RCC [18]
    miR-138-5p, miR-200b, miR-429, miR-508 Lung cancer [19][20]
    PD-L1 miR-142-5p PC, OC [21][22]
    miR-497-5p ccRCC [23]
    miR-20-b, miR-21, miR-130b, miR-138-5p, miR-148a-3p, miR-191-5p CRC [24][25][26][27]
    miR-195, miR-424-5p, miR-497, miR-873, miR-3609 BC [28][29][30][31]
    miR-17-5p, miR-146a Melanoma [32][33]
    miR-15a, miR-15b, miR-16, miR-193a-3p, miR-320a Pleural Mesothelioma [34][35]
    miR-155, miR-195, miR-214 B-cell lymphoma [36][37][38]
    miR-16, miR-195 Prostate cancer [39]
    miR-34a, miR-34b, miR-34c, miR-140, miR-200, miR-200a-3p, miR-3127-5p Lung cancer [40][41][42][43][44]
    miR-34a AML [45]
    miR-23a-3p, miR-570 Liver cancer [46][47]
    miR-375 HNSCC [48]
    miR-145 OC, bladder cancer [49][50]
    miR-513a-5p Retinoblastoma [51]
    miR-105-5p, miR-152, miR-200b, miR-200c, miR-570 GC [52][53][54][55][56]
    miR-18a, miR-140, miR-142, miR-340, miR-383 Cervical cancer [57]
    miR-217 Laryngeal cancer [58]
    miR-20b-5p Models of lung and BC [59]
    miR-194-5p PC [60]
    PD-L1+B7-H3 miR-326 Lung cancer [61]
    PD-1, CTLA-4 miR-424 OC [62]
    miR-138-5p Glioma [63]
    CD80/CTLA-4 miR-424 CRC [64]
    PD-1, PD-L1, CTLA-4 miR-33a Lung cancer [65]
    PD-1, BTLA, Tim-3 miR-28 Melanoma mouse model [66]
    BTLA miR-32 OC [67]
    Tim-3 miR-498 AML [68]
    IDO1 miR-153, miR-448 CRC [69][70]
    Gal-3 miR-424-3p OC [71]
    miR-128 CRC [72]
    Gal-9 miR-22 Liver cancer [73]
    miR-15b-5p, miR-455-5p, miR-1237, miR-1246 CRC [74][75]
    ICOS (B7-H2)/ICOSL miR-24 GC [76]
    B7-H3 miR-29 (a, b and c) Neuroblastoma, sarcoma, brain tumors [77]
    miR-145 Lung cancer [78]
    miR-28-5p, miR-29a, miR-128, miR-145, miR-155/miR-143, miR-187, miR-192, miR-335-5p, miR-378, miR-1301-3p CRC [79][80][81][82][83]
    miR-187 ccRCC [84]
    miR-29c Melanoma,
    CRC
    [85][86]
    miR-29c, miR-34b, miR-124a, miR-125b-2, miR-214, miR-297, miR-326, miR-363, miR-380-5p, miR-506, miR-555, miR-567, miR-593, miR-601, miR-665, miR-708, miR-885-3p, miR-940 BC [87]
    miR-539 Glioma [88]
    miR-124 Osteosarcoma [89]
    miR-506 Mantle cell lymphoma [90]
    miR-214 Multiple myeloma [91]
    miR-29, miR-1253 Medulloblastoma [92][93]
    miR-199a Cervical cancer [94]
    B7-H5 (VISTA, BTNL2) miR-125a-5p GC [95]
    B7-H4 (VTCN1) miR-155/miR-143, miR-1207 CRC [80][96]
    miR-7–5p, hsa-let-7c, hsa-let-7f-5p, miR-17–3p, miR-21–3p, miR-21–5p, miR-24–1-5p, miR-27b-3p, miR-31–3p, miR-31–5p, miR-33a-5p, miR-33b-5p, miR-122–3p, miR-130b-3p, miR-138–1-3p, miR-148a-3p, miR-149–3p, miR-183–3p, miR-186–5p, miR-196a-5p, hsa-miR-204–3p, miR-299–5p, miR-302a-3p, miR-302e, miR-335–3p, miR-335–5p, miR-361–5p, miR-374c-5p, miR-483–3p, miR-513a-5p, miR-519e-3p, miR-520d-5p, miR-525–5p, miR-615–3p, miR-642a-5p, miR-744–5p, miR-937, miR-1246, miRPlus-G1246–3p, miR-1260a, miR-1265, miR-1284, miR-1290, miR-1973, miR-2115–3p, miR-2116–5p, miR-3178, miR-3202, miR-3646, miR-3651, miR-3676–3p, miR-3685, miR-3686, miR-4258, miR-4279, miR-4284, miR-4288, miR-4290, miR-4306, miR-4324 PC [97]
    B7-H6 (NCR3LG1) miR-93, miR-195, miR-340 BC [29]
    B7-H7 (HHLA2) miR-3116, miR-6870-5p ccRCC [98]
    Footnotes: RCC—renal cell cancer; PC—pancreatic cancer; OC—ovarian cancer; CRC—colorectal cancer; BC—breast cancer; AML—acute myeloid leukemia; HNSCC—head and neck squamous cell cancer; GC—gastric cancer.

    2. The Features of Immune Checkpoint Gene Regulation by microRNA in Cancer

    The results of accumulated data analysis demonstrate a significant relationship between the action of miRNAs on ICs genes and the type of tumor—only about 14% (95% CI: 9.8–20.1%) of the studied miRNAs regulate the expression of specific IC in more than one type of cancer.

    Currently, there are numerous studies underway to identify miRNAs that are the most promising as immunotherapy agents. In vivo experiments have repeatedly shown that miRNA-based therapy leads to significant tumor regression. Although miRNA has not yet entered the arsenal of antitumor agents used in practice, some results are encouraging. Thus, the miR-155 inhibitor has performed well in clinical trials. The study of miR-138 is promising. Ongoing research on miR-34a may also lead to a positive result. Thus, there is the prospect of using miRNA as a therapeutic agent in cancer immunotherapy regimens. At the same time, the ability of miRNAs to inhibit several genes can lead to adverse events. To overcome this, it is important to expand data of the spectrum of miRNA targets in a particular type of cancer. Additional studies of the miRNA–genes interaction features and the search for an optimal miRNA mimic structure are necessary, thus allowing an increase in the efficiency and selectivity of interaction with the mRNA of target genes. It can increase the effectiveness of therapy, as well as reduce the dose of the drug, thereby reducing its side effects.

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      Kipkeeva, F.; Muzaffarova, T.; Korotaeva, A.; Mansorunov, D.; Apanovich, P.; Nikulin, M.; Malikhova, O.; Stilidi, I.; Karpukhin, A. Immune Checkpoint Gene Regulation by microRNA in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/26518 (accessed on 30 January 2023).
      Kipkeeva F, Muzaffarova T, Korotaeva A, Mansorunov D, Apanovich P, Nikulin M, et al. Immune Checkpoint Gene Regulation by microRNA in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/26518. Accessed January 30, 2023.
      Kipkeeva, Fatimat, Tatyana Muzaffarova, Alexandra Korotaeva, Danzan Mansorunov, Pavel Apanovich, Maxim Nikulin, Olga Malikhova, Ivan Stilidi, Alexander Karpukhin. "Immune Checkpoint Gene Regulation by microRNA in Cancer," Encyclopedia, https://encyclopedia.pub/entry/26518 (accessed January 30, 2023).
      Kipkeeva, F., Muzaffarova, T., Korotaeva, A., Mansorunov, D., Apanovich, P., Nikulin, M., Malikhova, O., Stilidi, I., & Karpukhin, A. (2022, August 25). Immune Checkpoint Gene Regulation by microRNA in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/26518
      Kipkeeva, Fatimat, et al. ''Immune Checkpoint Gene Regulation by microRNA in Cancer.'' Encyclopedia. Web. 25 August, 2022.
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