大 B 细胞淋巴瘤预处理微环境中 PD-L1+ 巨噬细胞和肿瘤细胞的丰度以及与 T 细胞的接近程度影响 CD19 CAR-T 细胞免疫疗法的疗效。

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-08-07 DOI:10.1002/hem3.142
Alexandre V. Hirayama, Jocelyn H. Wright, Kimberly S. Smythe, Salvatore Fiorenza, Akira N. Shaw, Jordan Gauthier, David G. Maloney, Kikkeri N. Naresh, Cecilia C. S. Yeung, Cameron J. Turtle
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引用次数: 0

摘要

CD19靶向嵌合抗原受体T细胞(CAR-T)免疫疗法改变了复发/难治性大B细胞淋巴瘤(LBCL)的治疗方法,但只有不到一半的患者能获得持久缓解。肿瘤微环境(TME)是影响 CD19 CAR-T 疗法疗效的一个关键因素,但对它的研究还不够。我们使用 NanoString nCounter 转录组图谱分析(n = 24)和多重免疫组化(mIHC,n = 15)研究了接受 CD19 CAR-T 疗法的 LBCL 患者治疗前活检中的肿瘤微环境。接受CAR-T疗法后获得完全应答(CR)的患者与T细胞迁移和功能相关的基因表达较高,而未获得CR的患者与巨噬细胞和T细胞功能障碍相关的基因表达较高。TME中免疫浸润和纤维化的不同模式与CAR-T疗法的结果有关,人工智能辅助图像分析证实了这些发现。获得CR的患者活检组织中免疫浸润的比例较低,细胞减少/纤维化区域的比例较高。此外,mIHC 显示非 CR 患者的 CD4+ T 细胞密度较低,而巨噬细胞和表达 PD-L1 的肿瘤细胞密度较高。空间分析显示,与接受CAR-T疗法后达到CR的患者相比,未达到CR的患者中PD-1+ T细胞与PD-L1+巨噬细胞或PD-L1+肿瘤细胞的距离较近。这些研究结果表明,治疗前活检组织中TME的形态模式和PD-1/PD-L1轴的参与可能会影响LBCL患者对CD19 CAR-T免疫疗法的反应。
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PD-L1+ macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B-cell lymphoma microenvironment impact CD19 CAR-T cell immunotherapy efficacy

CD19-targeted chimeric antigen receptor T-cell (CAR-T) immunotherapy has transformed the management of relapsed/refractory large B-cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR-T therapy outcomes. Using NanoString nCounter transcriptome profiling (n = 24) and multiplex immunohistochemistry (mIHC, n = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR-T therapy. Patients who achieved complete response (CR) after CAR-T therapy demonstrated higher expression of genes associated with T-cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T-cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR-T therapy outcomes, and these findings were corroborated using artificial intelligence-assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4+ T cells and higher densities of both macrophages and tumor cells expressing PD-L1 in non-CR patients. Spatial analysis revealed that PD-1+ T cells were in close proximity to PD-L1+ macrophages or PD-L1+ tumor cells in patients who did not compared to those who did achieve CR after CAR-T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD-1/PD-L1 axis in pretreatment biopsies may impact CD19 CAR-T immunotherapy response in patients with LBCL.

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来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
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