The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs.
miRNA | Cancer | miRNA Target Gene | ICI | Experimental Model | Effect on ICI Response | Refs. | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Experimental Effect on miRNA | Refs. | ||||||||||
let-7a and let-7b | Head and neck squamous cell carcinoma | TCF-4 * | anti CTLA-4 | Overexpressing let-7a/b tumor cells inoculated into mice + anti CTLA-4 | H | ||||||
anti PD-1 | miRNA analysis in peripheral lymphocytes from 21 good responders (complete response, partial response, or stable disease) with metastatic renal cell carcinoma before and after a 4-weeks period (2 cycles) of nivolumab administration | [ | 13 | ] | |||||||
miR-99a, miR-708, miR-655, miR-582-3p, miR-492, miR-487a, miR-485-3p, miR-449a, miR-433, miR-431, miR-429, miR-376c, miR-342-5p, miR-340, miR-339-5p, miR-335, miR-324-5p, miR-25, miR-24, miR-22, miR-221, miR-214, miR-194, miR-18b, miR-152, miR-143, miR-100, miR-let-7ev | High levels of expression in peripheral lymphocytes after treatment compared to before treatment in good responders. | [ | 31 | ][41] | miR-15b-5p | Colorectal cancer | PD-L1 * | anti PD-1 | Overexpressing miR-15b-5p tumor cells inoculated into mice + anti PD-1. | H | [14] |
miRNA analysis in peripheral lymphocytes from 17 good long-responders (complete response, partial response or stable disease and progression-free survival (PFS) > 18 months) with metastatic renal cell carcinoma before and after a 4-weeks period (2 cycles) of nivolumab administration | miR-22, miR-24, miR-99a, miR-194, miR-214, miR-335, miR-339, miR-708 | miR-16-5p | Lung cancer | anti PD-L1 | Tumor cell + overexpressing miR-16-5p exosomes + anti PD-L1 | H | [15] | ||||
High expression levels in peripheral lymphocytes after treatment compared to before treatment in good responders. | |||||||||||
anti CTLA-4 + anti PD-1 |
Plasma from stage IV melanoma non-responders (13 patients), partial response (4 patients) and complete response (5 patients) before and after Ipilimumab and Nivolumab/Pembrolizumab treatment | miR-4649-3p and miR-615-3p | Increased levels in post- vs. pre-treatment in non-responders. No changes post- vs. pre-treatment in patients with partial response. Decreased levels post- vs. pre-treatment in patients with complete response. | [32][42 | miR-20b-5p | Lung cancer | PD-L1 * | anti PD-1 | Tumor cells transfected with miRNA mimic + Pembrolizumab | H | [16] |
] | Breast cancer | Tumor cells transfected with miRNA mimic + Pembrolizumab | H | ||||||||
miR-21 | Oral squamous cell carcinoma | PTEN | anti PD-L1 | Tumor cells inoculated into mice + miR-21 knockdown tumor-derived exosomes + anti-PD-L1 | L | [17] | |||||
Melanoma | STAT1 * | anti PD-1 | Tumor cells and knocked down miR-21 tumor-associated macrophages (TAM) subcutaneously injected in mice + anti PD-1 | L | [18] | ||||||
miR-128a | Laryngeal squamous cell carcinoma | BMI1 * | anti PD-1 | Overexpressing miR-128a tumor cells + Pembrolizumab | H | [19] | |||||
miR-155 | Metastatic melanoma | anti PD-1 + anti PD-L1 + anti CTLA-4 |
Tumor cells inoculated into modified mice for knockout of miR-155 in CD4/8 T cells + anti PD-1, anti PD-L1 and anti CTLA-4 | L | [20] | ||||||
Diffuse large B-cell lymphoma | PD-L1 * | anti PD-L1 | Overexpressing miR-155 tumor cells inoculated into mice + anti PD-L1 | L | [21] | ||||||
Breast cancer | SOCS1 | anti PD-L1 | Overexpressing miR-155 tumor cells inoculated into mice + anti PD-L1 | H | [22] | ||||||
Melanoma | PD-L1 * | anti PD-L1 | Overexpressing miR-155 tumor cells co-cultured with peripheral blood mononuclear cells + anti PD-L1 | H | [23] | ||||||
miR-340 | Pancreatic carcinoma | CD47 * | anti CD47 | Overexpressing miR-340 tumor cells inoculated into mice + anti CD47 | L | [24] | |||||
miR-424 | Colorectal cancer | CD28 and CD80 * | anti PD-1 + anti CTLA-4 | Tumor cells inoculated into miR-424 knocked mice + anti PD-1 and anti CTLA-4 | L | [25] | |||||
Mouse cecum orthotopic colorectal cancer + miR-424 knocked tumor cell-derived extracellular vesicles + anti PD-1 and anti CTLA-4 | L | ||||||||||
Hepatocellular carcinoma | PD-L1 | anti PD-L1 | Tumor cells inoculated into mice + nanobubbles carrying miR-424 mimic and anti PD-L1 | H | [26] | ||||||
miR-582 | B-cell precursor acute lymphoblastic leukemia | CD276 * | anti CD276 | Overexpressing miR-582 tumor cells co-cultured with NK cells + anti CD276 | H | [27] | |||||
miR-708 | T-acute lymphoblastic leukemia | CD47 * | anti CD47 | Overexpressing miR-708 tumor cells + anti CD47. | H | [28] | |||||
miR-4759 | Breast cancer | PD-L1 * | anti PD-L1 | Overexpressing miR-4759 tumor cells co-cultured with peripheral blood mononuclear cells + anti PD-L1 | H | [29] |
ICI | Experimental Model | miRNA |
---|
Several miRNAs directly or indirectly regulate PD-L1 expression (Table 1). The let-7 family (let-7a, let-7b, let-7c, let-7d and let-7e) is thought to mediate tumor suppression in cancer by inhibiting tumor cell proliferation, promoting cell death evasion or metastasis [33][46] but also alterations to immunity. Let-7 was significantly downregulated in tissue from head and neck squamous cell carcinoma patients compared to healthy tissue [13][25]. Let-7 downregulation has been observed in other types of cancer associated with reduced copy numbers, such as melanoma [34][47], with an upregulation of LIN28A/LIN28B, which is an RNA binding protein that inhibits Drosha or Dicer binding during let-7 biogenesis (breast cancer) [35][48], and with DNA hypermethylation (epithelial ovarian cancer) [36][49].
miRNA | Cancer | miRNA Target Gene | ICI | Experimental Model | Effect on ICI Response | Refs. |
---|---|---|---|---|---|---|
let-7a and let-7b | Head and neck squamous cell carcinoma | TCF-4 * | anti CTLA-4 | Overexpressing let-7a/b tumor cells inoculated into mice + anti CTLA-4 | H | [25] |
miR-15b-5p | Colorectal cancer | PD-L1 * | anti PD-1 | Overexpressing miR-15b-5p tumor cells inoculated into mice + anti PD-1. | H | [26] |
miR-16-5p | Lung cancer | anti PD-L1 | Tumor cell + overexpressing miR-16-5p exosomes + anti PD-L1 | H | [27] | |
miR-20b-5p | Lung cancer | PD-L1 * | anti PD-1 | Tumor cells transfected with miRNA mimic + Pembrolizumab | H | [28] |
Breast cancer | Tumor cells transfected with miRNA mimic + Pembrolizumab | H | ||||
miR-21 | Oral squamous cell carcinoma | PTEN | anti PD-L1 | Tumor cells inoculated into mice + miR-21 knockdown tumor-derived exosomes + anti-PD-L1 | L | [29] |
Melanoma | STAT1 * | anti PD-1 | Tumor cells and knocked down miR-21 tumor-associated macrophages (TAM) subcutaneously injected in mice + anti PD-1 | L | [30] | |
miR-128a | Laryngeal squamous cell carcinoma | BMI1 * | anti PD-1 | Overexpressing miR-128a tumor cells + Pembrolizumab | H | [31] |
miR-155 | Metastatic melanoma | anti PD-1 + anti PD-L1 + anti CTLA-4 |
Tumor cells inoculated into modified mice for knockout of miR-155 in CD4/8 T cells + anti PD-1, anti PD-L1 and anti CTLA-4 | L | [32] | |
Diffuse large B-cell lymphoma | PD-L1 * | anti PD-L1 | Overexpressing miR-155 tumor cells inoculated into mice + anti PD-L1 | L | [33] | |
Breast cancer | SOCS1 | anti PD-L1 | Overexpressing miR-155 tumor cells inoculated into mice + anti PD-L1 | H | [34] | |
Melanoma | PD-L1 * | anti PD-L1 | Overexpressing miR-155 tumor cells co-cultured with peripheral blood mononuclear cells + anti PD-L1 | H | [22] | |
miR-340 | Pancreatic carcinoma | CD47 * | anti CD47 | Overexpressing miR-340 tumor cells inoculated into mice + anti CD47 | L | [35] |
miR-424 | Colorectal cancer | CD28 and CD80 * | anti PD-1 + anti CTLA-4 | Tumor cells inoculated into miR-424 knocked mice + anti PD-1 and anti CTLA-4 | L | [36] |
Mouse cecum orthotopic colorectal cancer + miR-424 knocked tumor cell-derived extracellular vesicles + anti PD-1 and anti CTLA-4 | L | |||||
Hepatocellular carcinoma | PD-L1 | anti PD-L1 | Tumor cells inoculated into mice + nanobubbles carrying miR-424 mimic and anti PD-L1 | H | [37] | |
miR-582 | B-cell precursor acute lymphoblastic leukemia | CD276 * | anti CD276 | Overexpressing miR-582 tumor cells co-cultured with NK cells + anti CD276 | H | [38] |
miR-708 | T-acute lymphoblastic leukemia | CD47 * | anti CD47 | Overexpressing miR-708 tumor cells + anti CD47. | H | [39] |
miR-4759 | Breast cancer | PD-L1 * | anti PD-L1 | Overexpressing miR-4759 tumor cells co-cultured with peripheral blood mononuclear cells + anti PD-L1 | H | [40] |