Keane Colm, Law Soi C, Gould Clare, Birch Simone, Sabdia Muhammed B, Merida de Long Lilia, Thillaiyampalam Gayathri, Abro Emad, Tobin Joshua W, Tan Xiaohong, Xu-Monette Zijun Y, Young Ken H, Gifford Grace, Gabreilli Sara, Stevenson William S, Gill Anthony, Talaulikar Dipti, Jain Sanjiv, Hernandez Annette, Halliday Sarah-Jane, Bird Robert, Cross Donna, Hertzberg Mark, Gandhi Maher K
Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Princess Alexandra Hospital, Brisbane, QLD, Australia.
Blood Adv. 2020 Apr 14;4(7):1367-1377. doi: 10.1182/bloodadvances.2019001390.
Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.
阻断PD - 1轴在弥漫性大B细胞淋巴瘤（DLBCL）中的疗效一般，但关于LAG3的数据却很稀少。我们检测了309例接受标准化疗免疫疗法治疗的DLBCL患者中LAG3数字基因表达的影响。通过免疫组织化学和流式细胞术确定LAG3蛋白的细胞分布。在肿瘤浸润淋巴细胞（TILs）中，LAG3在CD4 +调节性T细胞（Tregs）上表达最高，与CD4 +非Tregs相比，在CD8 + T细胞上也高表达（两者P = 0.008）。LAG3高表达的TILs中PD - 1和TIM - 3富集。LAG3也在一部分恶性B细胞上表达，并且这些患者活检组织中的LAG3信使核糖核酸显著更高（P = 0.03）。在发现/验证队列中，LAG3高表达与较差的生存率相关，与起源细胞和国际预后指数无关。PD - L1高表达的患者LAG3高表达的可能性高出五倍（P < 0.0001）。与LAG3低/PD - L1高表达的患者相比，LAG3高/PD - L1高表达的患者无进展生存期（P = 0.011）和总生存期（P = 0.005）较差。数字空间蛋白质分析证实LAG3在T细胞上表达，令人惊讶的是，在肿瘤微环境中，肿瘤相关巨噬细胞（TAM）上的LAG3表达水平高于CD20 + B细胞。LAG3经常在CD4 + Tregs和CD8 + TILs上表达，通常与其他免疫检查点一起，并且也存在于DLBCL的一部分恶性B细胞以及富含TAM的区域中。LAG3高表达与不良预后相关，与传统预后指标无关。
