miRNA-Based Therapeutics in the Era of Immune-Checkpoint Inhibitors

Huemer, Florian; Leisch, Michael; Geisberger, Roland; Zaborsky, Nadja; Greil, Richard

doi:10.3390/ph14020089

Cited by 11 publications

(10 citation statements)

References 102 publications

(69 reference statements)

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“…MiRNAs are important to regulate immune cell function, differentiation and interaction with the tumor microenvironment, and these functions have been subject of several recent reviews [ 67 , 68 ]. For instance, miRNAs such as miR-27a have been reported to alter tumor antigen presentation and colorectal cancer tumors with high miR-27a had reduced T cell infiltration.…”

Section: Main Textmentioning

confidence: 99%

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Leveraging epigenetics to enhance the efficacy of immunotherapy

Licht

Bennett

2021

Clin Epigenet

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Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

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Section: Main Textmentioning

confidence: 99%

“…For instance, miR-34 binds directly to the 3' untranslated region of PDL1 in non-small cell lung cancer cell lines to downregulate PDL-1 expression, resulting in enhanced T cell response [ 72 , 73 ]. Thus, miRNAs may be useful biomarkers in some contexts to predict response to immunotherapies [ 68 ].…”

Section: Main Textmentioning

confidence: 99%

Leveraging epigenetics to enhance the efficacy of immunotherapy

Licht

Bennett

2021

Clin Epigenet

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“…However, this section highlights some of the recent advancements in the utilization of ‘microRNAs’ in improving the efficacy of ICB-therapeutics. For example, miR-21, miR-34, miR-146a, miR-155 including many others miRNAs ( Table 3 ) [ 193 , 194 ] have shown astonishing results by targeting PD-1, PD-L1 and CTLA4 immune markers summarized well in these references [ 132 , 133 ].…”

Section: Micrornas and Epigenetic Modifiers (Dna And Histone Proteins) In Icb-therapymentioning

confidence: 99%

Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH

Kumar

Sarthi

Mani

et al. 2021

Cells

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Cellular immunotherapy has recently emerged as a fourth pillar in cancer treatment co-joining surgery, chemotherapy and radiotherapy. Where, the discovery of immune checkpoint blockage or inhibition (ICB/ICI), anti-PD-1/PD-L1 and anti-CTLA4-based, therapy has revolutionized the class of cancer treatment at a different level. However, some cancer patients escape this immune surveillance mechanism and become resistant to ICB-therapy. Therefore, a more advanced or an alternative treatment is required urgently. Despite the functional importance of epitranscriptomics in diverse clinico-biological practices, its role in improving the efficacy of ICB therapeutics has been limited. Consequently, our study encapsulates the evidence, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which can be reformed into RNA modifying drugs (RMD). Here, we have explained the mechanism of individual RNA-modifiers (editor/writer, eraser/remover, and effector/reader) in overcoming the issues associated with high-dose antibody toxicities and drug-resistance. Moreover, we have shed light on the importance of suppressor of cytokine signaling (SOCS/CISH) and microRNAs in improving the efficacy of ICB-therapy, with brief insight on the current monoclonal antibodies undergoing clinical trials or already approved against several solid tumor and metastatic cancers. We anticipate our investigation will encourage researchers and clinicians to further strengthen the efficacy of ICB-therapeutics by considering the importance of epitranscriptomics as a personalized medicine.

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“…On the other hand, inactivating mutations of TP53, which can be detected in approximately 20% of DLBCL patients [ 89 , 114 , 115 , 116 ], have been shown to increase PD-L1 expression in various tumour types [ 101 , 117 , 118 ] and might result in defective p53-regulated miRNA responses that normally control PD-L1 levels [ 119 , 120 ]. Indeed, noncoding RNAs that may target PD-L1, such as miR-34a [ 120 , 121 ] or miR-195 [ 122 ] in DLBCL, as well as other immune-checkpoints, are receiving increased attention [ 123 , 124 ]. Hypoxia, an inevitable hallmark of tumour microenvironment resulting from deprivation of oxygen due to the abnormal vasculature and tumour mass expansion, may also enforce gene expression reprogramming in DLBCL [ 125 ] and can induce PD-L1 expression [ 126 ].…”

Section: The Pd-1/pd-l1 Axis In Dlbclmentioning

confidence: 99%

The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

Garcia-Lacarte

Grijalba

Melchor

et al. 2021

Cancers

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Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (TFH) and regulatory T (TFR) or B (Breg) cells are involved in positive selection of GC B cells and may result critically in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of TFR cells and limiting IL-21-mediated anti-tumour functions of TFH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8+ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.

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miRNA-Based Therapeutics in the Era of Immune-Checkpoint Inhibitors

Cited by 11 publications

References 102 publications

Leveraging epigenetics to enhance the efficacy of immunotherapy

Leveraging epigenetics to enhance the efficacy of immunotherapy

Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH

The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

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