Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma.
Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma.
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DOI：
10.1073/pnas.2105822118
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发表时间：
2021-10-12
影响因子：
11.1
通讯作者：
Steidl C
中科院分区：
文献类型：
--
作者：
Aoki T;Chong LC;Takata K;Milne K;Marshall A;Chavez EA;Miyata-Takata T;Ben-Neriah S;Unrau D;Telenius A;Boyle M;Weng AP;Savage KJ;Scott DW;Farinha P;Shah SP;Nelson BH;Steidl C
我们的研究在单细胞分辨率下提供了LR-CHL微环境中免疫细胞的详细功能和空间特征。我们描述了详细的T细胞亚群定义，重要的是确定了一个独特的CD4+PD-1+CXCL13+CXCR5HFH样亚群，它环绕在−细胞周围，看起来非常接近CXCR5+B细胞，并与不良的临床结果相关。我们还发现了LR-CHL中独特的PD-1/PD-L1轴生物学，即HRS细胞上PD-L1基因改变与肿瘤微环境中PD-1蛋白表达呈负相关。重要的是，我们的发现有助于更深入地了解LR-CHL的细胞串扰，这可能有助于开发新的生物标记物和有针对性的治疗策略。富含淋巴细胞的经典型霍奇金淋巴瘤(LR-CHL)是霍奇金淋巴瘤的一种罕见亚型。最近的技术进步使得在CHL的肿瘤微环境(TME)中描述恶性霍奇金Reed-Sternberg(HRS)细胞和不同正常免疫细胞之间的特定串扰机制成为可能。然而，LR-CHL的TME还没有在单胞分辨率下得到表征。在这里，我们用单细胞RNA测序技术(scRNA-seq)检测了8例LR-CHL的细胞悬液标本，并与20例混合细胞型(MC，9例)和结节硬化型(NS，11例)CHL以及5例反应性淋巴结对照进行了比较。我们还对来自同一患者的组织微阵列进行了多色免疫荧光(MC-IF)，并对31例治疗前LR-CHL样本进行了独立的验证队列。ScRNA-seq分析发现LR-CHL中存在一个独特的CD4+辅助T细胞亚群，其特征是高表达趋化因子C-X-C基序配体13(CXCL13)和PD-1。与其他CHL亚型相比，LR-CHL中PD-1+CXCL13+T细胞显著丰富，空间分析显示在46%的LR-CHL病例中，这些细胞在HRS细胞周围形成花环。MC-IF分析显示，在LR-CHL中，CXCR5+正常B细胞与CXCL13+T细胞非常接近，且水平显著升高。此外，PD-1+CXCL13+T细胞在TME中的丰度与LR-CHL的无进展生存期显著相关(P=0.032)。综上所述，我们的研究结果强烈表明CXCL13/CXCR5轴和PD-1+CXCL13+T细胞作为LR-CHL的治疗靶点具有重要的致病意义。
Our study provides detailed functional and spatial characteristics of immune cells in the LR-CHL microenvironment at single-cell resolution. We describe detailed T cell subset definitions and importantly identified a unique CD4+PD-1+CXCL13+CXCR5− TFH-like subset that surrounds HRS cells, appears in close proximity to CXCR5+ B cells, and is associated with poor clinical outcome. We also uncovered unique PD-1/PD-L1 axis biology in LR-CHL, namely a negative correlation between PD-L1 genetic alterations on HRS cells and PD-1 protein expression in the tumor microenvironment. Importantly, our findings contribute to a deeper understanding of cellular cross-talk in LR-CHL, which may aid in the development of novel biomarkers and targeted treatment strategies. Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4+ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1+CXCL13+ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5+ normal B cells in close proximity to CXCL13+ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1+CXCL13+ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1+CXCL13+ T cells as a treatment target in LR-CHL.
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影响因子：
64.5
作者：
Levine JH;Simonds EF;Bendall SC;Davis KL;Amir el-AD;Tadmor MD;Litvin O;Fienberg HG;Jager A;Zunder ER;Finck R;Gedman AL;Radtke I;Downing JR;Pe'er D;Nolan GP
通讯作者：
Nolan GP
影响因子：
3
作者：
Klimatcheva E;Pandina T;Reilly C;Torno S;Bussler H;Scrivens M;Jonason A;Mallow C;Doherty M;Paris M;Smith ES;Zauderer M
通讯作者：
Zauderer M
影响因子：
16.6
作者：
Bunse M;Pfeilschifter J;Bluhm J;Zschummel M;Joedicke JJ;Wirges A;Stark H;Kretschmer V;Chmielewski M;Uckert W;Abken H;Westermann J;Rehm A;Höpken UE
通讯作者：
Höpken UE
影响因子：
45.3
作者：
Chan, Fong Chun;Mottok, Anja;Steidl, Christian
通讯作者：
Steidl, Christian
DOI：
10.1073/pnas.0706017104
发表时间：
2007-08-07
影响因子：
11.1
作者：
Juszczynski, Przemyslaw;Ouyang, Jing;Shipp, Margaret A.
通讯作者：
Shipp, Margaret A.