亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Sequential Scmultiomics of In Vivo CAR-T Cells Allows Characterization of Transcriptional Differences between Patients, and Identifies IL10 As a Potential Mechanism of Resistance to CAR-T Cells in MM

CD8型 嵌合抗原受体 转录组 细胞毒性T细胞 T细胞 免疫疗法 生物 CD28 免疫系统 免疫学 癌症研究 医学 基因表达 体外 基因 遗传学
作者
Juan R. Rodríguez-Madoz,Lorea Jordana-Urriza,Guillermo Serrano,Aina Oliver‐Caldés,María Eréndira Calleja-Cervantes,Patxi San-Martin,Amaia Vilas–Zornoza,Asier Ullate‐Agote,Aintzane Zabaleta,Diego Alignani,Teresa Lozano,Valentín Cabañas Perianes,Juan Luís Reguera,Almudena Navarro‐Bailón,Marta Español‐Rego,Mariona Pascal,José M. Moraleda,José Antonio Pérez‐Simón,María‐Victoria Mateos,Fermin Sanchez-Guijo Martin,Álvaro Urbano‐Ispizua,Manel Juan,Ana Alfonso Piérola,J. Rifón,Paula Rodríguez‐Otero,Bruno Paiva,Susana Inogés,Ascensión López‐Díaz de Cerio,Juan José Lasarte,Jesús F. San Miguel,Carlos Fernández de Larrea,Mikel Hernáez,Felipe Prósper
出处
期刊:Blood [American Society of Hematology]
卷期号:142 (Supplement 1): 3433-3433 被引量:1
标识
DOI:10.1182/blood-2023-182887
摘要

Background: CAR-T cells have revolutionized cancer immunotherapy, representing a promising option for R/R Multiple Myeloma (MM). Despite high remission rates observed after BCMA CAR-T therapy, many patients still relapse and knowledge of the molecular mechanisms governing CAR-T cell function is very limited. To shed some light on specific transcriptomic programs activated after CAR-T cell administration, we interrogated longitudinal samples of CAR-T cells collected from patients enrolled in CARTBCMA-HCB-01 (NCT04309981) and academic clinical trial in patients with RRMM (Oliver-Caldes A, et al. Lancet Oncol, 2023). Methodology: We characterized 50.805 CAR-T cells from 11 different samples collected from 3 patients, including final infusion products (IP) and CAR-T cells isolated from bone marrow (BM) and peripheral blood (PB), at one and three months after infusion. Single-cell RNA and TCR sequencing was performed using Chromium Single-Cell Immune Profiling solution from 10x Genomics, which allows simultaneous analysis of gene expression and paired T-cell receptors. Gene Regulatory Network (GRN) analysis was performed using SimiC, a novel machine learning method developed by our group, that infers regulatory dissimilarities from single cell data (Peng J, et al. Commun Biol., 2022) Results: scRNA-seq revealed that although CAR-T cells from IP presented similar profiles, with highly proliferative CD4 + and CD8 + memory cells, CAR-T cells remaining after infusion were mainly non-proliferating CD8 + cells, with effector/effector-memory phenotypes. Interestingly, transcriptomic profile of CAR-T cells differed among patients with different degrees of response. Partial responders presented increased presence of terminally differentiated effector cells with an exhausted signature, while complete responders presented CAR-T cells in transition to central or effector memory phenotype. Additionally, we found that BM and PB CAR-T cells presented different phenotypes, potentially due to abrogated regulatory mechanisms. Specifically, CAR-T cells infiltrating BM presented increased expression of cytotoxic and exhaustion markers compared to their PB counterparts. GRN analysis with SimiC identified several regulons ( PRDM1, ARID4B) with increased activity in CAR-T cells from BM, which could be responsible for these differences. PRDM1 has already been associated with CAR-T cell exhaustion and its depletion promotes TCF7-dependent CAR-T cell stemness and proliferation. ARID4B, a chromatin remodeler, could be acting as an epigenetic regulator of CAR-T cell function. Importantly, combination of scTCR-seq and scRNA-seq allowed the identification of a hyperexpanded CAR-T clone, with immunosuppressor features, mainly present in the BM of a patient with partial response. Deeper characterization showed that this clone had higher expression of cytotoxic and activation markers, with increased expression of IL10. Further analysis with SimiC showed association of IL10 with transcription factors related to exhausted CD8 + T cells, like CREM, BHLHE40 or PRDM1, also implicated in the production of IL10 in Treg. Additional in vitrostudies suggested that subsequent activation of endogenous TCR after CAR-T cell activation led to IL10 production, and functional validations corroborated that IL10 reduces CAR-T cell functionality. Conclusions: Overall, our analysis combining scRNA-seq/scTCR-seq with novel machine learning models, allowed us to characterize key transcriptional differences observed between patients, infusion products and in vivo infused CAR-T, as well as between CAR-T according to their location (PB vs. BM). Importantly, our results identify IL10 as a regulatory mechanism promoting CAR-T cell dysfunction, representing a potential target to be modulated for the development of improved CAR-T therapies for MM.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
efren1806完成签到,获得积分10
10秒前
1分钟前
天行健完成签到,获得积分10
2分钟前
陆林北完成签到,获得积分10
3分钟前
3分钟前
3分钟前
4分钟前
小韩同学完成签到,获得积分10
4分钟前
4分钟前
5分钟前
5分钟前
6分钟前
小牛发布了新的文献求助10
6分钟前
6分钟前
小牛完成签到,获得积分10
6分钟前
Wang完成签到 ,获得积分20
7分钟前
7分钟前
neurology完成签到,获得积分10
7分钟前
neurology发布了新的文献求助10
7分钟前
wtsow完成签到,获得积分0
7分钟前
7分钟前
7分钟前
田様应助科研通管家采纳,获得10
7分钟前
8分钟前
淡淡的幻然关注了科研通微信公众号
9分钟前
9分钟前
9分钟前
非洲大象完成签到,获得积分10
9分钟前
hzc应助科研通管家采纳,获得10
9分钟前
10分钟前
别找了睡觉吧完成签到 ,获得积分10
10分钟前
10分钟前
hzc应助科研通管家采纳,获得10
11分钟前
hzc应助科研通管家采纳,获得10
11分钟前
hzc应助科研通管家采纳,获得10
11分钟前
11分钟前
冷安发布了新的文献求助10
12分钟前
Chenmengdan应助wangsiheng采纳,获得10
13分钟前
13分钟前
zydd发布了新的文献求助10
13分钟前
高分求助中
The ACS Guide to Scholarly Communication 2500
Sustainability in Tides Chemistry 2000
Studien zur Ideengeschichte der Gesetzgebung 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Threaded Harmony: A Sustainable Approach to Fashion 810
Pharmacogenomics: Applications to Patient Care, Third Edition 800
Gerard de Lairesse : an artist between stage and studio 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3081574
求助须知:如何正确求助?哪些是违规求助? 2734422
关于积分的说明 7532772
捐赠科研通 2383886
什么是DOI,文献DOI怎么找? 1264087
科研通“疑难数据库(出版商)”最低求助积分说明 612563
版权声明 597578