Greenbaum Adam M, Fromm Jonathan R, Gopal Ajay K, Houghton A McGarry
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
Blood Res. 2022 Jun 30;57(2):117-128. doi: 10.5045/br.2022.2021145. Epub 2022 May 13.
B-cell non-Hodgkin lymphomas (NHL) are hematologic malignancies that arise in the lymph node. Despite this, the malignant cells are not cleared by the immune cells present. The failure of anti-tumor immunity may be due to immune checkpoints such as the PD-1/PDL-1 axis, which can cause T-cell exhaustion. Unfortunately, unlike Hodgkin lymphoma, checkpoint blockade in NHL has shown limited efficacy.
We performed an extensive functional analysis of malignant and non-malignant lymph nodes using high dimensional flow cytometry. We compared follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and lymph nodes harboring reactive hyperplasia (RH).
We identified an expansion of CD8+PD1+ T-cells in the lymphomas relative to RH. Moreover, we demonstrate that these cells represent a mixture of activated and exhausted T-cells in FL. In contrast, these cells are nearly universally activated and functional in DLBCL. This is despite expression of counter-regulatory molecules such as PD-1, TIM-3, and CTLA-4, and the presence of regulatory T-cells.
These data may explain the failure of single-agent immune checkpoint inhibitors in the treatment of DLBCL. Accordingly, functional differences of CD8+ T-cells between FL and DLBCL may inform future therapeutic targeting strategies.
B 细胞非霍奇金淋巴瘤（NHL）是起源于淋巴结的血液系统恶性肿瘤。尽管如此，现存的免疫细胞并不能清除恶性细胞。抗肿瘤免疫失败可能归因于免疫检查点，如 PD-1/PDL-1 轴，其可导致 T 细胞耗竭。不幸的是，与霍奇金淋巴瘤不同，NHL 中的检查点阻断疗效有限。
我们使用高维流式细胞术对恶性和非恶性淋巴结进行了广泛的功能分析。我们比较了滤泡性淋巴瘤（FL）、弥漫性大 B 细胞淋巴瘤（DLBCL）和伴有反应性增生（RH）的淋巴结。
我们发现相对于 RH，淋巴瘤中 CD8+PD1+ T 细胞扩增。此外，我们证明这些细胞在 FL 中代表活化和耗竭 T 细胞的混合物。相比之下，这些细胞在 DLBCL 中几乎普遍被激活且具有功能。尽管存在如 PD-1、TIM-3 和 CTLA-4 等负调节分子的表达以及调节性 T 细胞的存在。
这些数据可能解释了单药免疫检查点抑制剂治疗 DLBCL 失败的原因。因此，FL 和 DLBCL 之间 CD8+ T 细胞的功能差异可能为未来的治疗靶向策略提供依据。
