Enhancing adoptive T cell immunotherapy with microRNA therapeutics

Ji, Yun; Hocker, James D.; Gattinoni, Luca

doi:10.1016/j.smim.2015.11.006

Cited by 35 publications

(29 citation statements)

References 130 publications

(210 reference statements)

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“…Consistent with our study, increasing evidence has demonstrated that extracellular miRNAs play critical roles in the development, differentiation and function of a variety of immune cells, including B and T lymphocytes, dendritic cells, and macrophages . The ability of miRNAs to target multiple molecules in signalling pathways and their involvement in regulating various aspects of T‐cell biology make them attractive molecules to exploit for more effective adoptive T‐cell therapies .…”

Section: Discussionsupporting

confidence: 90%

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Exosomal miR‐24‐3p impedes T‐cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma

Zhang

Cai

et al. 2016

The Journal of Pathology

207

139

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Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4 and CD8 T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 90%

“…Role of exosomal miR-24 in immune regulation of nasopharyngeal carcinoma 339 in regulating various aspects of T-cell biology make them attractive molecules to exploit for more effective adoptive T-cell therapies [31,32].…”

Section: Role Of Exosomal Mir-24 In Immune Regulation Of Nasopharyngementioning

confidence: 99%

Exosomal miR‐24‐3p impedes T‐cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma

Zhang

Cai

et al. 2016

The Journal of Pathology

207

139

View full text Add to dashboard Cite

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“…However, trafficking, survival, and persistence of reinfused T cells need to be optimized, and genetic engineering of T cells is an approach currently explored to improve T-cell qualities. In particular, genetic manipulation of specific microRNAs may allow improvement of T-cell fitness (5). microRNAs are $22nt long noncoding RNAs that posttranscriptionally regulate protein expression.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma

Martinez-Usatorre

Sempere

Carmona

et al. 2019

Cancer Immunology Research

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microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8 þ T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8 þ T cells. In B16 tumors expressing a low-affinity antigen ligand, tumorspecific infiltrating CD8 þ T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti-PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8 þ T cells. In addition, miR-155 overexpression enhanced exhausted CD8 þ T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8 þ T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8 þ tumorinfiltrating T cells may be a surrogate marker of the relative potency of in situ antigen-specific CD8 þ T-cell responses.

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“…A deficiency of Dicer in T cells leads to the dysregulation of CD8 + T cell activation, proliferation and survival, indicating that miRNAs are major gene regulators during CD8 + T cell responses [28]. Therefore, the properties of miRNAs may be particularly relevant for the long-term survival of adoptively transferred T cells [29]. Extensive studies have indeed provided a comprehensive view of the expression and functionality of several [30,31].…”

Section: Biological Characteristics Of Mirnas In Cd8 + T Cellsmentioning

confidence: 99%

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

Zhang

et al. 2018

Cell Physiol Biochem

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MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8⁺ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8⁺ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8⁺ T cells. We specifically discuss the effect of miRNAs on key transcription factors, immune checkpoints and signal pathways, which contribute to the differentiation of effector and memory T cell subsets. Ultimately, miRNAs may be easily integrated into existing T cell receptor (TCR) and chimeric antigen receptor (CAR) platforms to promote adoptive T cell therapy with multiple advantages. Thus, combining T cell-based therapy with miRNAs could be considered a promising and robust strategy for cancer treatment.

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Enhancing adoptive T cell immunotherapy with microRNA therapeutics

Cited by 35 publications

References 130 publications

Exosomal miR‐24‐3p impedes T‐cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma

Exosomal miR‐24‐3p impedes T‐cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma

MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

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