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，但在不到一半的治疗患者中观察到持久缓解。肿瘤微环境 (TME) 是影响 CD19 CAR-T 治疗结果的关键且尚未得到研究的因素。使用 NanoString nCounter 转录组分析 (n = 24) 和多重免疫组织化学 (mIHC，n = 15)，我们研究了接受 CD19 CAR-T 治疗的 LBCL 患者的治疗前活检中的 TME。 CAR-T 治疗后达到完全缓解 (CR) 的患者表现出与 T 细胞运输和功能相关的基因表达较高，而未达到 CR 的患者则与巨噬细胞和 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独特模式与 CAR-T 治疗结果相关，这些发现通过人工智能辅助图像分析得到了证实。达到 CR 的患者活检中散布免疫浸润的比例较低，而细胞减少/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，而表达 PD-L1 的巨噬细胞和肿瘤细胞密度较高。空间分析显示，与 CAR-T 治疗后达到 CR 的患者相比，未达到 CR 的患者的 PD-1 T 细胞与 PD-L1 巨噬细胞或 PD-L1 肿瘤细胞非常接近。这些发现表明，TME 的形态模式以及治疗前活检中 PD-1/PD-L1 轴的参与可能会影响 LBCL 患者的 CD19 CAR-T 免疫治疗反应。© 2024 作者。约翰·威利 (John Wiley) 出版的 HemaSphere

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.© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.