CD39/CD73/A2AR pathway and cancer immunotherapy

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: March 2, 2023

Abstract Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 CD73 play critical roles in reshaping an TME. accumulated mediates its regulatory functions binding to one four receptors (A1R, A2AR, A2BR A3R). A2AR elicits profound function via regulating cAMP signaling. increasing evidence suggests CD39, could be used as novel therapeutic targets for manipulating the immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting CD39/CD73/A2AR pathway have been investigated clinical trials single agents combination anti-PD-1/PD-L1 therapies. this review, we provide updated summary about pathophysiological adenosinergic cancer development, metastasis drug resistance. more components therapy circumvention immunotherapy resistance are also discussed. Emerging biomarkers may guide selection CD39/CD73/A2AR-targeting treatment strategies individual patients deliberated.

Language: Английский

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Targeting TIGIT for cancer immunotherapy: recent advances and future directions

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Jan. 16, 2024

Abstract As a newly identified checkpoint, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is highly expressed on CD4 + cells, CD8 natural killer (NK) regulatory cells (Tregs), tumor-infiltrating lymphocytes (TILs). TIGIT has been associated NK exhaustion in vivo individuals various cancers. It not only modulates survival but also mediates exhaustion. the primary ligand of humans, CD155 may be main target for immunotherapy due to its interaction TIGIT. found that anti-programmed death protein 1 (PD-1) treatment response cancer correlated Anti-TIGIT alone combination anti-PD-1 agents have tested immunotherapy. Although two clinical studies advanced lung had positive results, TIGIT-targeted antibody, tiragolumab, recently failed new trials. In this review, we highlight current developments discuss characteristics functions

Language: Английский

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Overcoming tumor resistance mechanisms in CAR-NK cell therapy

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 3, 2022

Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs severe toxicities described for cells. Permanently scrutinized its efficacy, recent promising data clinical trials point out achievement deep, high-quality responses, thus confirming potential use. Although is not significantly affected by loss or downregulation CAR tumor target, case cell, plethora common additional intrinsic extrinsic mechanisms that could also disable NK function have been described. Therefore, considering lessons learned from therapy, emergence resistance can be envisioned. In this review we highlight processes involved development, focusing on cytokine addiction fratricide during manufacturing, poor trafficking, exhaustion within microenvironment (TME), short vivo persistence account limited expansion, replicative senescence, rejection patient’s immune system after lymphodepletion recovery. Finally, outline new actively explored alternatives to overcome these mechanisms, special emphasis CRISPR/Cas9 mediated genetic engineering approaches, platform optimize eradicate cancers.

Language: Английский

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TIGIT blockade repolarizes AML-associated TIGIT⁺M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(12), P. e004794 - e004794

Published: Dec. 1, 2022

Background Leukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about phenotype, function, and plasticity of these cells. The present study provides extensive characterization in patients with acute myeloid leukemia (AML). Methods phenotype expression coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM blood aspirates obtained from newly diagnosed (pAML, n=59), long-term remission (lrAML, n=8), relapsed (rAML, n=7) monocyte-derived healthy donors (HD, n=17). subpopulations correlated clinical parameters. Using a blocking anti-T-cell immunoreceptor Ig ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion cytokines, phagocytosis LAMs vitro. Results In pAML rAML, M1 reduced predominant macrophage consisted immunosuppressive M2 defined by CD163, CD204, CD206, CD86. active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin mucin-domain containing-3 protein (TIM-3), lymphocyte-activation gene 3 (LAG-3). High CD163 was associated poor overall survival (OS). addition, increased frequencies TIGIT + intermediate adverse risk according to European Leukemia Network criteria FLT3 ITD mutation. vitro blockade shifted polarization primary peripheral blood-derived toward M1-associated cytokines chemokines. Moreover, augmented anti-CD47-mediated lines Conclusion Our findings suggest that can be redirected into efficient effector may direct relevance near future.

Language: Английский

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The Immune Regulatory Role of Adenosine in the Tumor Microenvironment

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14928 - 14928

Published: Oct. 5, 2023

Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities inducing cell proliferation, migration invasion, tissue angiogenesis, chemoresistance. In addition, plays important role regulating anti-tumor immune responses facilitating escape. Adenosine receptors are broadly expressed tumor-infiltrated cells, including suppressive tumor-associated macrophages CD4+ regulatory T as well effector CD8+ cytotoxic lymphocytes. Therefore, indispensable down-regulating contributes to progression. This review describes current progress on adenosine/adenosine receptor pathway tumor-infiltrating that contribute evasion aims provide insights into adenosine-targeted immunotherapy.

Language: Английский

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CAR-NK cells in combination therapy against cancer: A potential paradigm

Heliyon, Journal Year: 2024, Volume and Issue: 10(5), P. e27196 - e27196

Published: Feb. 29, 2024

Various preclinical and a limited number of clinical studies CAR-NK cells have shown promising results: efficient elimination target without side effects similar to CAR-T therapy. However, the homing infiltration abilities are poor due inhibitory tumor microenvironment. From perspective treatment strategies, combined with biological microenvironment characteristics NK cells, combination therapy strategies anti-PD-1/PD-L1, radiotherapy chemotherapy, kinase inhibitors, proteasome STING agonist, oncolytic virus, photothermal therapy, can greatly promote proliferation, migration cytotoxicity cells. In this review, we will summarize targets selection, structure constructions combinational therapies for tumors provide feasible overcoming improving efficacy

Language: Английский

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CD39 – A bright target for cancer immunotherapy

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 151, P. 113066 - 113066

Published: May 10, 2022

The ATP-adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumor microenvironment, cancer immune evasion largely involves generation high amounts immunosuppressive extracellular adenosine (eADO). Consequently, inhibition eADO-generating enzymes and/or eADO receptors can effectively restore antitumor multiple cells. With several clinical strategies currently being explored to modulating in patients with cancer, recent data antagonists targeting CD73 A2A receptor have demonstrated promising therapeutic potential cancer. Recent findings reveal that ectonucleotidase CD39, limiting enzyme been viewed "immunological switch", converts ATP-driven pro-inflammatory milieu an anti-inflammatory state mediated by adenosine. Owing its superior feature CD39 antagonism rely not only on preventing accumulation but also stabilization ATP immunity, inhibitors trials based are evaluated. there is focus understanding role governing how this alter potential. We herein review impact microenvironment treatment preference. Additionally, we discuss implication for rational combination therapies, molecular regulation, well limitations.

Language: Английский

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Preclinical Evaluation of CRISPR-Edited CAR-NK-92 Cells for Off-the-Shelf Treatment of AML and B-ALL

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12828 - 12828

Published: Oct. 24, 2022

Acute myeloid leukemia (AML) and B-cell acute lymphocytic (B-ALL) are severe blood malignancies affecting both adults children. Chimeric antigen receptor (CAR)-based immunotherapies have proven highly efficacious in the treatment of leukemia. However, challenge immune escape cancer cells remains. The development more affordable ready-to-use therapies is essential view costly time-consuming preparation primary cell-based treatments. In order to promote antitumor function against AML B-ALL, we transduced NK-92 with CD276-CAR or CD19-CAR constructs. We also attempted enhance cytotoxicity by a gene knockout three different inhibitory checkpoints NK cell (CBLB, NKG2A, TIGIT) CRISPR-Cas9 technology. antileukemic activity generated lines was tested calcein luciferase-based assays various lines. Both CAR-NK-92 exhibited targeted significant boost comparison parental NK-92. knock-outs did not improve B-ALL cytotoxicity. triple knock-out CD276-CAR-NK-92 cells, as well CBLB TIGIT showed significantly enhanced U-937 CD19/tag These results indicate that lines' cytotoxic performance suitable for killing, making them promising off-the-shelf therapeutic candidates. should be further investigated AML.

Language: Английский

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TIGIT Expression on Activated NK Cells Correlates with Greater Anti-Tumor Activity but Promotes Functional Decline upon Lung Cancer Exposure: Implications for Adoptive Cell Therapy and TIGIT-Targeted Therapies

Cancers, Journal Year: 2023, Volume and Issue: 15(10), P. 2712 - 2712

Published: May 11, 2023

Treatments targeting TIGIT have gained a lot of attention due to strong preclinical and early clinical results, particularly with anti-PD-(L)1 therapeutics. However, this combination has failed meet progression-free survival endpoints in phase III trials. Most our understanding comes from studies T cell function. Yet, inhibitory receptor is often upregulated the same, or higher, extent on NK cells cancers. Studies murine models demonstrated that inhibits promotes exhaustion, its effects tumor control also being dependent cells. there are limited assessing role function human (hNK), lung cancer. used lines tested blockade reactivate exhausted obtained cancer patients. For therapeutic advancement, better context activated hNK crucial, which different than cells, critical adoptive therapeutics may be combined blockade. In study, effect anti-tumor activities ex vivo-expanded was evaluated vitro expression higher and/or expanded compared resting More

Language: Английский

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The role of exhausted natural killer cells in the immunopathogenesis and treatment of leukemia

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 22, 2024

Abstract The immune responses to cancer cells involve both innate and acquired cells. In the meantime, most attention has been drawn adaptive cells, especially T while, it is now well known that natural killer (NK) play a vital role in defending against malignancies. While are trying eliminate malignant try prevent function of these suppress responses. suppression NK various cancers can lead induction an exhausted phenotype which will impair their function. Recent studies have shown occurrence this types leukemic malignancies affect prognosis disease, targeting may be considered new immunotherapy method treatment leukemia. Therefore, detailed study diseases help understand mechanisms leukemia progression design methods by creating deeper understanding Here, we comprehensively review immunobiology

Language: Английский

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