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细胞与髓系细胞的浸润是肿瘤微环境的关键特征，但当前尚未纳入治疗决策考量。本研究采用多重免疫荧光显微技术，针对260余例弥漫性大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）的免疫浸润程度，结合临床结局、基因突变谱和表型特征进行量化分析。研究发现MCL是免疫浸润最“冷”的亚型，而DLBCL则呈现最“热”的免疫状态。DLBCL的淋巴瘤微环境中，CD8+ T细胞与滤泡辅助性T细胞（Tfh）在数量上占主导地位，且其富集与良好预后相关。在CD8+ T细胞浸润较低的DLBCL中，EZH2、PTEN及KMT2D基因突变呈现过表达特征。DLBCL的独特之处在于其浸润大量PDL1阳性巨噬细胞，该类细胞可占总细胞数的70%。PDL1阳性巨噬细胞浸润与调节性T细胞浸润呈互斥关系。在同源免疫活性模型中，诱导性清除巨噬细胞上的PDL1即可显著提升对MYC表达淋巴瘤的免疫控制效果。这些结果表明，巨噬细胞/CD8+ T细胞轴是部分预后不良DLBCL患者的关键致病决定因素及免疫治疗靶点。
肿瘤(癌症)患者之家