Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia

Cox, Michelle J.; Lucien, Fabrice; Sakemura, Reona; Boysen, Justin C.; Kim, Young S.; Horvei, Paulina; Roman, Claudia Manriquez; Hansen, Michael J.; Tapper, Erin E.; Siegler, Elizabeth L.; Forsman, Cynthia L.; Crotts, Sydney B.; Schick, Kendall J.; Hefazi, Mehrdad; Ruff, Michael W.; Can, İsmail; Adada, Mohamad M.; Bezerra, Evandro D.; Fonkoua, Lionel Aurelien Kankeu; Nevala, Wendy K.; Braggio, Esteban; Ding, Wei; Parikh, Sameer A.; Kay, Neil E.; Kenderian, Saad S.

doi:10.1016/j.ymthe.2020.12.033

Cited by 50 publications

(42 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We identified a plethora of immune checkpoints (ICs) carried by the CLL-EVs (including the ectonucleotidases CD39 and CD73, PD-L1, TGFβ, the TIM3 ligand galectin-9, and the TIGIT ligand CD112) that could explain the observed effects on T-cells. Ultimately, we confirm and append previous findings about the detrimental influence of CLL-EVs on CAR-T-cell function [ 17 ]. Our novel findings on CLL-EVs could contribute to developing the means for restoring T-cell immunity in CLL.…”

Section: Introductionsupporting

confidence: 89%

“…Furthermore, CLL-EVs were studied in terms of intercellular communication between the malignant B-cells and their microenvironment including monocytes [ 15 ] and stroma cells [ 16 ]. However, only a few studies examining the effects of CLL-derived EVs on T-cells are available including a manuscript presenting evidence of the inhibitory properties of CLL-EVs on CD19-directed CAR-T-cell therapy [ 17 ], which will be discussed here as well.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints

Böttcher-Loschinski

Kahlfuß

Aigner

et al. 2022

Cells

View full text Add to dashboard Cite

Background: Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of malignant B-cells and multiple immune defects. This leads, among others, to severe infectious complications and inefficient immune surveillance. T-cell deficiencies in CLL include enhanced immune(-metabolic) exhaustion, impaired activation and cytokine production, and immunological synapse malformation. Several studies have meanwhile reported CLL-cell–T-cell interactions that culminate in T-cell dysfunction. However, the complex entirety of their interplay is incompletely understood. Here, we focused on the impact of CLL cell-derived vesicles (EVs), which are known to exert immunoregulatory effects, on T-cell function. Methods: We characterized EVs secreted by CLL-cells and determined their influence on T-cells in terms of survival, activation, (metabolic) fitness, and function. Results: We found that CLL-EVs hamper T-cell viability, proliferation, activation, and metabolism while fostering their exhaustion and formation of regulatory T-cell subsets. A detailed analysis of the CLL-EV cargo revealed an abundance of immunological checkpoints (ICs) that could explain the detected T-cell dysregulations. Conclusions: The identification of a variety of ICs loaded on CLL-EVs may account for T-cell defects in CLL patients and could represent a barrier for immunotherapies such as IC blockade or adoptive T-cell transfer. Our findings could pave way for improving antitumor immunity by simultaneously targeting EV formation or multiple ICs.

show abstract

Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints

Böttcher-Loschinski

Kahlfuß

Aigner

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…Exosomes have been previously well studied in the context of the immune response, and scholars have proposed many mechanisms that explain how cancer cells promote immune escape and cancer development [18,87,88]. Several studies have pointed out that tumor-derived exosomes realized immune escape by inhibiting the activation of immune cells, causing a functional loss in immune responses [89][90][91][92]. Dendritic cells (DCs) serve as the most critical antigen-presenting cells (APCs) of the human immune system, and they function by promoting the expression of Toll-like receptors (TLRs) and generating multiple interleukins (ILs).…”

Section: Immune Escapementioning

confidence: 99%

The significance of exosomal RNAs in the development, diagnosis, and treatment of pancreatic cancer

Zhao

Yang

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

Exosomes are single-membrane, secreted organelles with a diameter of 30–200 nm, containing diverse bioactive constituents, including DNAs, RNAs, proteins, and lipids, with prominent molecular heterogeneity. Extensive studies indicate that exosomal RNAs (e.g., microRNAs, long non-coding RNAs, and circular RNAs) can interact with many types of cancers, associated with several hallmark features like tumor growth, metastasis, and resistance to therapy. Pancreatic cancer (PaCa) is among the most lethal cancers worldwide, emerging as the seventh foremost cause of cancer-related death in both sexes. Hence, revealing the specific pathogenesis and improving the clinical diagnosis and treatment process are urgently required. As the study of exosomes has become an active area of research, the functional connections between exosomes and PaCa have been deeply investigated. Among these, exosomal RNAs seem to play a significant role in the development, diagnosis, and treatment of PaCa. Exosomal RNAs delivery ultimately modulates the various features of PaCa, and many scholars have interpreted how exosomal RNAs contribute to the proliferation, angiogenesis, migration, invasion, metastasis, immune escape, and drug resistance in PaCa. Besides, recent studies emphasize that exosomal RNAs may serve as diagnostic and prognostic biomarkers or therapeutic targets for PaCa. In this review, we will introduce these recent insights focusing on the discoveries of the relationship between exosomal RNAs and PaCa, and the potentially diagnostic and therapeutic applications of exosomes in PaCa.

show abstract

“…Another group used single-cell RNA sequencing on brain tissue to try to determine the cause of neurotoxicity. They found a very small subset of CD19 + cells in the brain that also expressed CD248, indicating that they were mural cells [30] . While it is not yet known whether these mural cells are specifically responsible for neurotoxicity, it is possible that they are targeted once the blood brain barrier is disrupted during treatment.…”

Section: Transcriptomic Analysis To Uncover Mechanisms Of Cart Cell Toxicitiesmentioning

confidence: 99%

Omics analyses provide insights to CART cell therapy resistance

Cox¹,

Kenderian²

2021

JTGG

Self Cite

View full text Add to dashboard Cite

Chimeric antigen receptor T (CART) cell therapy has revolutionized the treatment of relapsed/refractory B cell malignancies in recent years. Despite high initial response rates, durable response rates are low, and CART cell efficacy in solid tumors is very modest. Additionally, the overall success of CART cell therapy is limited by toxicities such as cytokine release syndrome and neurotoxicity. Decades of advancement in genome sequencing technology and bioinformatics have given us a better understanding of how cancer develops and evolves following treatments. This has resulted in a better understanding of patient response to cancer treatment on a molecular level. Resistance to CART cell therapy can be mediated by the cancer cells, the tumor microenvironment, or the patient's T cells. In this review, we will outline lessons learned from multi-omics studies (1) to identify biomarkers of response or toxicity to CART cell therapy or (2) to develop biomarker-guided therapeutic interventions to overcome these limitations.

show abstract

Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia

Cited by 50 publications

References 47 publications

CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints

CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints

The significance of exosomal RNAs in the development, diagnosis, and treatment of pancreatic cancer

Omics analyses provide insights to CART cell therapy resistance

Contact Info

Product

Resources

About