Stopeck A T, Gessner A, Miller T P, Hersh E M, Johnson C S, Cui H, Frutiger Y, Grogan T M
Department of Medicine, Arizona Cancer Center, University of Arizona, Tucson 85724, USA.
Clin Cancer Res. 2000 Oct;6(10):3904-9.
Tumor-infiltrating CD8+ T-lymphocytes (T-TILs) are thought to be relevant to immunosurveillance of several tumor types including B-cell non-Hodgkin's lymphoma. B- and T-lymphocyte interactions via cellular adhesion molecules (CAMs), recognition molecules (HLAs), and costimulatory molecules (CSMs) are necessary for optimal antigen-specific T-cell activation to occur and may be important in generating effective host T-TIL responses. We previously found that low T-TIL response (CD8+ T cells < 6%) correlates with statistically shorter relapse-free survival in patients with diffuse large-cell lymphoma (DLCL). We now extend our observations in 71 DLCL patients by analyzing malignant B-cell expression of the following molecules important in T-cell activation: (a) recognition molecules [MHC I (MAS and MCA) and MHC II (HLA-DR, -DP, -DQ)]; (b) CAMs [leukocyte function antigen 1 (CD11a and CD18) and intracellular adhesion molecule 1 (CD54)]; and (c) CSMs [B7.1 (CD80) and B7.2 (CD86)]. Eighteen patients (25%) had low a T-TIL response, and 53 patients (75%) had a high T-TIL response. Overall, expression of the MHC class H molecules HLA-DR and HLA-DQ was most conserved. The loss of B7.2 (P = 0.04), intracellular adhesion molecule 1 (P = 0.0004), MAS (P = 0.02), and HLA-DR (P = 0.0004) expression was significantly associated with decreased T-TIL response. In 100% of patients with low T-TIL responses, at least one HLA, CAM, or CSM was undetectable on the malignant B cells by immunohistochemical staining (mean number of molecules lost = 2.67). In contrast, 49% of patients with high T-TIL responses had no losses in HLA, CAM, or CSM expression (mean number of molecules lost = 0.89). The mean number of absent molecules (HLA, CAM, or CSM) was significantly associated with T-TIL response (P = 0.0001). We conclude that loss of HLA, CAM, or CSM expression on malignant B cells is associated with a poor host T-cell immune response. In addition, because patients with low T-TIL response had lost expression of multiple cellular adhesion, recognition, and costimulatory molecules, our results suggest that a combination of immunorestorative therapies may be required to generate effective antitumor T-cell responses in B-cell DLCL.
肿瘤浸润性CD8 + T淋巴细胞（T-TILs）被认为与包括B细胞非霍奇金淋巴瘤在内的多种肿瘤类型的免疫监视有关。B淋巴细胞和T淋巴细胞通过细胞粘附分子（CAMs）、识别分子（HLAs）和共刺激分子（CSMs）进行相互作用，对于最佳抗原特异性T细胞激活的发生是必要的，并且在产生有效的宿主T-TIL反应中可能很重要。我们之前发现，低T-TIL反应（CD8 + T细胞<6%）与弥漫性大细胞淋巴瘤（DLCL）患者无复发生存期在统计学上显著缩短相关。我们现在通过分析在T细胞激活中重要的以下分子在恶性B细胞中的表达，扩展了对71例DLCL患者的观察：（a）识别分子[MHC I（MAS和MCA）和MHC II（HLA-DR、-DP、-DQ）]；（b）CAMs[白细胞功能抗原1（CD11a和CD18）和细胞间粘附分子1（CD54）]；以及（c）CSMs[B7.1（CD80）和B7.2（CD86）]。18例患者（25%）有低T-TIL反应，53例患者（75%）有高T-TIL反应。总体而言，MHC II类分子HLA-DR和HLA-DQ的表达最保守。B7.2（P = 0.04）、细胞间粘附分子-1（P = 0.0004）、MAS（P = 0.02）和HLA-DR（P = 0.0004）表达的缺失与T-TIL反应降低显著相关。在100%低T-TIL反应的患者中，通过免疫组织化学染色在恶性B细胞上至少检测不到一种HLA、CAM或CSM（丢失分子的平均数 = 2.67）。相比之下，49%高T-TIL反应的患者在HLA、CAM或CSM表达上没有缺失（丢失分子的平均数 = 0.�9）。缺失分子（HLA、CAM或CSM）的平均数与T-TIL反应显著相关（P = 0.0001）。我们得出结论，恶性B细胞上HLA、CAM或CSM表达的缺失与宿主T细胞免疫反应不良相关。此外，由于低T-TIL反应的患者失去了多种细胞粘附、识别和共刺激分子的表达，我们的结果表明，可能需要联合免疫恢复疗法来在B细胞DLCL中产生有效的抗肿瘤T细胞反应。
