Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer.
Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models.
The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors.
Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors.
IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.
Liu C
，Liu R
，Wang B
，Lian J
，Yao Y
，Sun H
，Zhang C
，Fang L
，Guan X
，Shi J
，Han S
，Zhan F
，Luo S
，Yao Y
，Zheng T
，Zhang Y
... -
《Journal for ImmunoTherapy of Cancer》
A scoping review on the potentiality of PD-L1-inhibiting microRNAs in treating colorectal cancer: Toward single-cell sequencing-guided biocompatible-based delivery.
Tumoral programmed cell death ligand 1 (PD-L1) has been implicated in the immune evasion and development of colorectal cancer. Although monoclonal immune checkpoint inhibitors can exclusively improve the prognosis of patients with microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) colorectal cancer, specific tumor-suppressive microRNAs (miRs) can regulate multiple oncogenic pathways and inhibit the de novo expression of oncoproteins, like PD-L1, both in microsatellite stable (MSS) and MSI-H colorectal cancer cells. This scoping review aimed to discuss the currently available evidence regarding the therapeutic potentiality of PD-L1-inhibiting miRs for colorectal cancer. For this purpose, the Web of Science, Scopus, and PubMed databases were systematically searched to obtain peer-reviewed studies published before 17 March 2021. We have found that miR-191-5p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, miR-140-3p, and miR-15b-5p can inhibit tumoral PD-L1 in colorectal cancer cells. Besides inhibiting PD-L1, miR-140-3p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, and miR-15b-5p can substantially reduce tumor migration, inhibit tumor development, stimulate anti-tumoral immune responses, decrease tumor viability, and enhance the chemosensitivity of colorectal cancer cells regardless of the microsatellite state. Concerning the specific, effective, and safe delivery of these miRs, the single-cell sequencing-guided biocompatible-based delivery of these miRs can increase the specificity of miR delivery, decrease the toxicity of traditional nanoparticles, transform the immunosuppressive tumor microenvironment into the proinflammatory one, suppress tumor development, decrease tumor migration, and enhance the chemosensitivity of tumoral cells regardless of the microsatellite state.
Shadbad MA
，Asadzadeh Z
，Derakhshani A
，Hosseinkhani N
，Mokhtarzadeh A
，Baghbanzadeh A
，Hajiasgharzadeh K
，Brunetti O
，Argentiero A
，Racanelli V
，Silvestris N
，Baradaran B
... -
《-》
MicroRNA-124-3p suppresses PD-L1 expression and inhibits tumorigenesis of colorectal cancer cells via modulating STAT3 signaling.
Programmed death ligand 1 (PD-L1) plays a significant role in colorectal tumorigenesis through induction of regulatory T cells (Tregs) and suppression of antitumor immunity. Furthermore, microRNAs (miRNAs) as the posttranscriptional regulators of gene expression show considerable promise as a therapeutic target for colorectal cancer (CRC) treatment. Considering this, in vitro effects of miRNA-124 (miR-124-3p) on CRC cell tumorigenesis and Tregs differentiation via targeting PD-L1 were investigated in the current study. Functional analysis showed that miR-124 is significantly downregulated in CRC tissues as compared with marginal normal samples (p < .0001), and its downregulation was negatively correlated with PD-L1 expression. Moreover, a specific region in PD-L1 3'-untranslated region was predicted as the miR-124 target and validated using the luciferase assay. Further investigation showed that transfection of HT29 and SW480 cells with miR-124 mimics significantly reduced PD-L1 mRNA, protein, and cell surface expression, and inhibited Tregs in coculture models via modulating interleukin [IL]-10, IL-2, tumor necrosis factor α, transforming growth factor beta, and interferon gamma expression levels. Besides, miR-124 overexpression decreased CRC cell proliferation and arrested cell cycle at the G1 phase through downregulation of c-Myc and induced apoptosis in CRC cells via upregulation of both intrinsic and extrinsic pathways. Also, miR-124 exogenous overexpression could reduce colony and spheroid formation ability of CRC cells via downregulating CD44 mRNA expression. miR-124 also diminished MMP-9 expression and subsequently suppressed cell migration and invasion. We also illustrated that STAT3 signaling was repressed by miR-124 in CRC cells. Taken together, our findings imply that considering the involvement of miR-124 in the regulation of PD-L1 through colorectal tumorigenesis and its remarkable antitumor effects, this miRNA could be regarded as the promising target for the development of therapeutic approaches for colorectal cancer.
Roshani Asl E
，Rasmi Y
，Baradaran B
《-》
ResearchGate
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