Chen Benjamin J, Dashnamoorthy Ravi, Galera Pallavi, Makarenko Vladislav, Chang Hong, Ghosh Srimoyee, Evens Andrew M
Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Oncotarget. 2019 Mar 12;10(21):2030-2040. doi: 10.18632/oncotarget.26771.
Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. TIM-3 showed positive staining on tumor cells in 39% of DLBCL cases and PD-L1 expression was noted in 15% of cases. Both PD-1 and LAG-3 were positive on tumor cells in a minority of DLBCL cases (8.3% and 7.5%, respectively), but were more widely expressed on TILs in a correlated manner. With median follow-up of 44 months ( = 70, range 5-85), 4-year progression-free survival (PFS) and overall survival (OS) rates were significantly inferior among DLBCL patients with high vs low/negative TIM-3 expression (PFS: 23% [95% CI 7% to 46%] vs 60% [95% CI 43% to 74%], respectively, = 0.008; OS: 30% [95% CI 10% to 53%] vs 74% [95% CI 58% to 85%], respectively, = 0.006). Differences in OS remained significant when controlling for International Prognostic Index in Cox regression analyses (HR 3.49 [95% CI 1.40-6.15], = 0.007). In addition, we observed that co-culture of DLBCL cell lines with primed T cells in the presence of anti-LAG-3 and anti-TIM-3 induced potent dose-dependent increases in cell death via AcellaTox and IL-2 ELISA assays, suggesting potent anti-tumor activity of these compounds.
通过免疫检查点受体发出的信号可能导致T细胞耗竭，并在癌症中作为免疫逃逸机制发挥作用。对于弥漫性大B细胞淋巴瘤（DLBCL），这些标志物在肿瘤细胞和肿瘤微环境中的机制及预后重要性仍不清楚。我们测定了123例DLBCL患者肿瘤细胞及肿瘤浸润淋巴细胞（TILs）上PD-1、PD-L1、TIM-3和LAG-3的免疫组化表达。39%的DLBCL病例中TIM-3在肿瘤细胞上呈阳性染色，15%的病例中观察到PD-L1表达。少数DLBCL病例中PD-1和LAG-3在肿瘤细胞上呈阳性（分别为8.3%和7.5%），但在TILs上以相关方式更广泛表达。中位随访44个月（n = 70，范围5 - 85），TIM-3高表达与低/阴性表达的DLBCL患者中，4年无进展生存期（PFS）和总生存期（OS）率显著较差（PFS：分别为23% [95% CI 7%至46%] 对60% [95% CI 43%至74%]，P = 0.008；OS：分别为30% [95% CI 10%至53%] 对74% [95% CI 58%至85%]，P = 0.006）。在Cox回归分析中控制国际预后指数时，OS差异仍显著（HR 3.49 [95% CI 1.40 - 6.15]，P = 0.007）。此外，我们观察到在抗LAG-3和抗TIM-3存在的情况下，DLBCL细胞系与致敏T细胞共培养通过AcellaTox和IL-2 ELISA检测诱导细胞死亡呈强效剂量依赖性增加，表明这些化合物具有强效抗肿瘤活性。
