Seeley B M, Barthel S W, To W C, Kjaergaard J, Shu S, Plautz G E
Center for Surgery Research, the Cleveland Clinic Foundation, OH, USA.
Otolaryngol Head Neck Surg. 2001 Apr;124(4):436-41. doi: 10.1067/mhn.2001.114253.
Animal tumor models have demonstrated that adoptive transfer of tumor-draining lymph node (TDLN) T lymphocytes can cure established tumors in many anatomic sites. However, subcutaneous tumors are relatively refractory and have required maximally tolerated doses of cells. The goals of this study were to determine whether a subset of TDLN T lymphocytes varying in expression of the cell adhesion molecule L-selectin (CD62L) had augmented therapeutic efficacy and to determine the co-stimulatory requirements for trafficking and anti-tumor effector function.
TDLNs were recovered from mice bearing progressive MCA 205 fibrosarcomas, and the T lymphocytes were segregated into CD62L(low) and CD62L(high) subsets and activated ex vivo with anti-CD3 mAb and IL-2. Mice bearing established subcutaneous MCA 205 tumors were treated with activated T cell subsets and in some experiments with additional mAb against cell adhesion molecules.
Adoptive transfer of as few as 5 x 10(6) activated cells cured mice bearing 3-day subcutaneous MCA 205 tumors initiated with 6 x 10(6) cells, and the tumors demonstrated a dense infiltrate of CD62L(low) cells. In marked contrast, adoptive transfer of 10 times as many T cells derived from the reciprocal CD62L(high) compartment had no effect on tumor growth. The effector function of the CD62L(low) T cells was clearly dependent on co-stimulation through the cell adhesion molecule LFA-1, because anti-LFA-1 mAb completely abrogated the anti-tumor reactivity of the transferred cells against subcutaneous tumors and inhibited tumor infiltration. In contrast, blockade of ICAM-1, VLA-4, or VCAM-1 had no inhibitory effect on the anti-tumor function.
These studies demonstrate the high therapeutic activity of the CD62L(low) subset of tumor-draining LN T cells against subcutaneous tumors, a relatively refractory site, and confirm the essential role of LFA-1 for effector T cell function.
Identification of the phenotype and requirements for effector function of T lymphocytes sensitized to tumor antigens has implications for clinical trials of adoptive immunotherapy for head and neck carcinoma using a similar approach.
动物肿瘤模型已表明，过继转移肿瘤引流淋巴结（TDLN）T淋巴细胞可治愈许多解剖部位已形成的肿瘤。然而，皮下肿瘤相对难治，需要使用最大耐受剂量的细胞。本研究的目的是确定细胞黏附分子L-选择素（CD62L）表达不同的TDLN T淋巴细胞亚群是否具有增强的治疗效果，并确定其迁移和抗肿瘤效应功能的共刺激需求。
从携带进展期MCA 205纤维肉瘤的小鼠中获取TDLN，将T淋巴细胞分离为CD62L（低）和CD62L（高）亚群，并在体外用抗CD3单克隆抗体和白细胞介素-2激活。用激活的T细胞亚群治疗已形成皮下MCA 205肿瘤的小鼠，在一些实验中还使用了抗细胞黏附分子的额外单克隆抗体。
仅5×10⁶个激活细胞的过继转移就治愈了接种6×10⁶个细胞起始的3日龄皮下MCA 205肿瘤的小鼠，且肿瘤显示有密集的CD62L（低）细胞浸润。形成鲜明对比的是，来自相对的CD62L（高）亚群的10倍数量的T细胞的过继转移对肿瘤生长没有影响。CD62L（低）T细胞的效应功能明显依赖于通过细胞黏附分子LFA-1的共刺激，因为抗LFA-1单克隆抗体完全消除了转移细胞对皮下肿瘤的抗肿瘤反应性并抑制了肿瘤浸润。相比之下，阻断ICAM-1、VLA-4或VCAM-1对抗肿瘤功能没有抑制作用。
这些研究证明了肿瘤引流淋巴结T细胞的CD62L（低）亚群对皮下肿瘤（一个相对难治的部位）具有高治疗活性，并证实了LFA-1对效应T细胞功能的重要作用。
鉴定对肿瘤抗原致敏的T淋巴细胞的表型和效应功能需求，对采用类似方法对头颈部癌进行过继免疫治疗的临床试验具有启示意义。
