Immune Checkpoints and microRNAs

Background

In recent years, there has been notable advancement in the field of cancer treatment with the use of immune checkpoint inhibitors (ICIs). Nevertheless, a substantial portion of patients fail to achieve sustained and optimal clinical outcomes through immunotherapy alone. Creative Biolabs regards the exploration of combination regimens as a novel and dynamic research focal point.

MicroRNAs (miRNAs), a class of endogenous small non-coding RNAs consisting of 18 to 25 nucleotides, play pivotal roles in the regulation of both physiological and pathological processes. Mounting evidence supports their function as pivotal immune modulators in the context of tumors. Notably, miRNAs, whether acting as tumor suppressors or oncogenes, have been observed to modulate anti-tumor immunity or facilitate communication between tumor cells and the immune milieu.

Furthermore, it is worth highlighting that a single miRNA can target multiple checkpoint molecules, mirroring the therapeutic effect of combined immune checkpoint blockade (ICB). Consequently, miRNA therapy is being considered as a strategy to enhance the efficacy of ICIs. Moreover, miRNAs hold promise as predictive and prognostic biomarkers, as well as therapeutic targets in the realm of immunotherapy.

Fig. 1 Interconnected miRNA network orchestrates direct regulation of immune checkpoint molecule expression.¹

Advantages of Immune Checkpoint Therapy with Gene Therapy

A single miRNA has demonstrated its ability to simultaneously target numerous checkpoint molecules, mirroring the therapeutic impact of a combined approach to ICB. The integration of microRNA therapy with ICB holds the potential to enhance the effectiveness of the established monotherapeutic paradigm.

The inherent capability of these concise transcripts to engage with multiple molecules, whether they belong to the same pathway or disparate pathways, engenders a synergistic, comprehensive impact. Consequently, the prudent selection of miRNAs targeting multiple immune checkpoint molecules emerges as the most judicious strategy.
The noteworthy attributes of C-miRNA, including its robust stability, accessibility, and noninvasive nature, have propelled it into the forefront of preclinical interest.

Case Study


Fig. 2 Key microRNAs orchestrating multifaceted immune checkpoint control.² Identification of miRNAs with multifaceted regulation of immune checkpoints in breast cancer cells for prospective immunotherapeutic utilization, including miR-93-5p with potential impact on PD-L1, PD-L2, and B7-H6; miR-149-3p targeting PD-1, TIM-3, and BTLA; and miR-195/miR-497 modulation of PD-L1 and B7-H6 expression.
	Fig. 3 Emerging insights unveil miRNAs as key regulators of immune responses in tumors.³ Contrary to earlier knowledge of miRNA primarily governing tumor cell biology, current research has unveiled a novel perspective wherein tumor-associated miRNAs exert influence over anti-tumor immune responses. Furthermore, these miRNAs have been found to mediate intricate interplays between tumor cells and the surrounding immune milieu, shedding light on the mechanisms responsible for their dysregulation during the course of tumorigenesis.
	Fig. 4 The involvement of immuno-modulatory miRNAs in orchestrating immune cell functions, immune checkpoint control, oncogenesis, progression, and diagnostic implications in cancer.⁴ MicroRNAs orchestrate diverse facets of the anti-tumor immune response, encompassing immune checkpoint molecules (PD-1, PD-L1, and CTL-A4), immune cell populations (macrophages, MDSCs, and NK cells), and the machinery governing tumor antigen processing. These findings suggest that miRNAs may represent the pivotal connecting element in the quest for potential biomarkers capable of prognosticating the efficacy of immune checkpoint inhibitors in tumor responses.

Services

Creative Biolabs provides a comprehensive range of tailored services pertaining to immune checkpoints, encompassing, yet not confined to: Immune Checkpoint Antibody Development, Immune Checkpoint Assays, Immune Checkpoint Targeted Peptide Development, etc. Please contact us for a thorough understanding.

References

Dragomir, Mihnea, et al. "Key questions about the checkpoint blockade-are microRNAs an answer?" Cancer biology & medicine 15.2 (2018): 103.
Zhou, Huiling, et al. "MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment." Cancers 15.3 (2023): 824.
Xing, Yun, et al. "MicroRNAs: immune modulators in cancer immunotherapy." Immunotherapy Advances 1.1 (2021): ltab006.
Omar, Hany A., et al. "Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment." The FEBS journal 286.18 (2019): 3540-3557.

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