Cui Ningxuan, Leary Peter, Ivanova Vanesa-Sindi, Stirm Kristin, Kirsche Lydia, Aceto Nicola, Stenner Frank, Dieterich Lothar C, Detmar Michael, Petrova Ekaterina, Mundt Sarah, Greter Melanie, Tzankov Alexandar, Müller Anne
Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
Functional Genomics Center Zürich, University of Zürich and Federal Institute of Technology Zürich, Zürich, Switzerland.
Blood Cancer J. 2025 Apr 16;15(1):66. doi: 10.1038/s41408-025-01281-1.
The infiltration of diffuse large- and other mature B-cell lymphomas with T- and myeloid cells is a key tumor microenvironmental feature but is not currently factored into treatment decisions. Here, we have used multiplex immunofluorescence microscopy to quantify the immune infiltrates of >260 diffuse large B-cell- (DLBCL), follicular- (FL) and mantle cell lymphomas (MCL), and chronic lymphocytic leukemias (CLL) relative to clinical outcomes, mutational landscape and phenotype. MCL were found to be the "coldest" and DLBCL the "hottest" entities. The lymphoma microenvironment of DLBCL featured numerically dominant populations of CD8 and T-follicular helper (Tfh) T-cells that were indicative of superior prognosis. Mutations in EZH2, PTEN and KMT2D were overrepresented in DLBCL with low CD8 T-cell infiltration. A unique feature of DLBCL was its infiltration by large numbers of PDL1 macrophages that constituted up to 70% of total cellularity. PDL1 macrophage infiltration was mutually exclusive with regulatory T-cell infiltration. The inducible ablation of PDL1 on macrophages was sufficient to improve immune control of MYC-expressing lymphoma in a syngeneic immunocompetent model. These results implicate the macrophage/CD8 T-cell axis as a key pathogenetic determinant and immunotherapeutic target in a subset of DLBCL patients with poor prognosis.
弥漫性大B细胞淋巴瘤及其他成熟B细胞淋巴瘤中T细胞和髓样细胞的浸润是关键的肿瘤微环境特征，但目前尚未纳入治疗决策考量。在此，我们运用多重免疫荧光显微镜技术，针对超过260例弥漫性大B细胞淋巴瘤（DLBCL）、滤泡性淋巴瘤（FL）、套细胞淋巴瘤（MCL）及慢性淋巴细胞白血病（CLL），就其免疫浸润情况与临床结局、突变图谱及表型进行了量化分析。结果发现MCL是“最冷”的淋巴瘤类型，而DLBCL是“最热”的。DLBCL的淋巴瘤微环境以数量上占主导的CD8和滤泡辅助性T细胞（Tfh）群体为特征，这预示着较好的预后。在CD8 T细胞浸润低的DLBCL中，EZH2、PTEN和KMT2D的突变更为常见。DLBCL的一个独特特征是有大量PDL1巨噬细胞浸润，其占总细胞数的比例高达70%。PDL1巨噬细胞浸润与调节性T细胞浸润相互排斥。在同基因免疫活性模型中，巨噬细胞上PDL1的诱导性消融足以改善对表达MYC的淋巴瘤的免疫控制。这些结果表明，巨噬细胞/CD8 T细胞轴是一部分预后不良的DLBCL患者关键的致病决定因素和免疫治疗靶点。
