Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 6, 2023

Abstract Despite the intense CD8+ T-cell infiltration in tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit efficacy here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that carcinoma enhance development suppressive activity regulatory T via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression thus reinvigorate immunity. Anti-CD70+ therapy is evaluated xenograft-derived organoids humanized mice, exhibiting improved tumor-killing efficacy. Mechanistically, knockout inhibits collective lipid signaling network CD4+ naïve involving mitochondrial integrity, cholesterol homeostasis, fatty acid metabolism. Furthermore, ATAC-Seq delineates transcriptionally upregulated NFKB2 Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ as metabolic switch enforces lipid-driven development, functional specialization Tregs, leading to evasion. This study also demonstrates blockade can act synergistically with treatment immunity against carcinoma.

Language: Английский

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Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment

Cancers, Journal Year: 2023, Volume and Issue: 15(10), P. 2718 - 2718

Published: May 11, 2023

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either monotherapies in combinatorial regimens. However, a considerable proportion patients do not respond experience early relapse, due to multiple parameters that contribute melanoma resistance. The expression other checkpoints beyond molecules remains major mechanism evasion. recent anti-LAG-3 ICI, relatlimab, combination with nivolumab disease, has capitalized on extensive research field highlighted potential further improvement prognosis by synergistically blocking additional targets new ICI-doublets, antibody-drug conjugates, novel modalities. Herein, we provide comprehensive overview presently published molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 B7-H3. Beginning from their immunomodulatory properties co-inhibitory co-stimulatory receptors, present all therapeutic modalities targeting these tested preclinical clinical settings. Better understanding checkpoint-mediated crosstalk between effector cells is essential generating more strategies augmented response.

Language: Английский

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IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Feb. 9, 2024

Abstract Background It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due its stringent expression pattern tissue apparent role tumor progression a considerable amount malignancies. Moreover, also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy CRC PDAC. We explored therapeutic potential target CAR natural killer (NK) therapy CRC, PDAC, focusing cells CAFs, lymphoma. Methods RNA-seq data immunohistochemical analysis patient samples were used explore PDAC patients. In addition, CD70-targeting NK developed assess cytotoxic activity against + effect cytokine stimulation their was evaluated. The vitro functionality CD70-CAR investigated panel CAF lines varying expression. Lymphoma-bearing mice validate vivo potency cells. Lastly, consider variability, tested patient-derived organoids containing CAFs. Results this study, we identified CAFs Functional evaluation CD70-directed indicated IL-15 essential effective elimination improve burden survival bearing tumors. Mechanistically, resulted improved upregulating increasing secretion pro-inflammatory cytokines, mainly autocrine or intracellular manner. Conclusions disclose an attractive both hematological armored act potent effectors eliminate these They can patients potentially other desmoplastic

Language: Английский

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ImmunoPET/CT imaging of clear cell renal cell carcinoma with [18F]RCCB6: a first-in-human study

European Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2024, Volume and Issue: 51(8), P. 2444 - 2457

Published: March 14, 2024

Language: Английский

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CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells

Cell Reports Medicine, Journal Year: 2025, Volume and Issue: unknown, P. 101889 - 101889

Published: Jan. 1, 2025

Language: Английский

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METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(10), P. 2265 - 2279

Published: Aug. 30, 2023

Language: Английский

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Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors

Leukemia, Journal Year: 2024, Volume and Issue: 38(6), P. 1323 - 1333

Published: March 16, 2024

Abstract Extramedullary multiple myeloma (EMM) is an aggressive form of (MM). This study represents the most comprehensive next-generation sequencing analysis EMM tumors ( N = 14) to date, uncovering key molecular features and describing tumor microenvironment. We observed co-occurrence 1q21 gain/amplification MAPK pathway mutations in 79% samples, suggesting that these are crucial mutational events development. also demonstrated patients with mutated KRAS at time diagnosis have a significantly higher risk development (HR 2.4, p 0.011) using data from large CoMMpass dataset. identified downregulation CXCR4 enhanced cell proliferation, along reduced expression therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy immunotherapy. Conversely, we upregulated EZH2 CD70 as potential future options. For first time, report on microenvironment EMM, revealing CD8+ T cells NK predominant immune effector single-cell sequencing. Finally, this longitudinal changes relapse.

Language: Английский

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Cancer drug-tolerant persister cells: from biological questions to clinical opportunities

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(10), P. 694 - 717

Published: Sept. 2, 2024

Language: Английский

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CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(10), P. 1879 - 1900

Published: June 20, 2024

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being key component. Yet, impact domains on downstream signaling and subsequent functionality CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated various CAR-NK cell using CD70-targeting CAR. We found that CD28, molecule not inherently present mature NK cells, significantly enhanced antitumor efficacy long-term cytotoxicity both vitro multiple xenograft models hematologic solid tumors. Mechanistically, showed CD28 linked to CD3ζ creates platform recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) zeta-chain-associated 70 (ZAP70), initiating cascade enhances function. Our study provides insights into how costimulation function supports its incorporation NK-based CARs for cancer immunotherapy. Significance: demonstrated T-cell-centric which is normally absent construct kinases including results persistence sustained cytotoxicity.

Language: Английский

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CD70-specific CAR NK cells expressing IL-15 for the treatment of CD19-negative B-cell malignancy

Blood Advances, Journal Year: 2024, Volume and Issue: 8(11), P. 2635 - 2645

Published: April 2, 2024

Abstract Chimeric antigen receptor (CAR) natural killer (NK) cells can eliminate tumors not only through the ability of CAR molecule to recognize antigen-expressed cancer but also NK-cell receptors themselves. This overcomes some limitations T cells, paving way for NK safer and more effective off-the-shelf cellular therapy. In this study, CD70-specific (a pan-target lymphoma) fourth-generation with 4-1BB costimulatory domain interleukin-15 (IL-15) was constructed transduced into cord blood–derived by Baboon envelope pseudotyped lentiviral vector. CD70-CAR displayed superior cytotoxic activity in vitro vivo against CD19-negative B-cell lymphoma when compared nontransduced CD19-specific cells. Importantly, mice that received 2 doses showed eradication tumors, accompanied increased concentration plasma IL-15 enhanced cell proliferation persistence. Our study suggests repetitive administration-based therapy has clinical advantage a single dose treatment lymphoma.

Language: Английский

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