Aruga A, Shu S, Chang A E
University of Michigan Medical Center, Ann Arbor 48109, USA.
Cancer Immunol Immunother. 1995 Nov;41(5):317-24. doi: 10.1007/BF01517220.
In this study, cytokine release by tumor-draining lymph node cells sensitized in vitro (IVS-TDLN) was examined and correlated with therapeutic efficacy in adoptive immunotherapy. Mice bearing immunologically distinct MCA 207 and MCA 205 sarcoma tumors were utilized in criss-cross experiments. IVS-TDLN obtained from mice bearing 10-day subcutaneous (s.c.) tumors mediated immunologically specific regression of established 3-day pulmonary metastases, but demonstrated non-specific cytolytic reactivity against both tumors in a 4-h 51Cr-release assay. By contrast, these IVS-TDLN cells were found specifically to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) when restimulated in vitro with irradiated tumor cells. To determine the predictive value of tumor-specific cytokine release with in vivo therapeutic efficacy, a kinetic analysis of antitumor activities of TDLN obtained from animals bearing MCA 207 tumors for increasing lengths of time was performed. IVS-TDLN cells from mice bearing day-7, -10 and -14 s.c. tumors manifested tumor-specific release of GM-CSF and IFN gamma, and mediated significant antitumor reactivity in vivo. In contrast IVS-LN cells from day-0 and day-21 tumor-bearing animals did not release significant amounts of GM-CSF and IFN gamma, and were not therapeutically efficacious in vivo. Day-4 IVS-TDLN released high levels of GM-CSF and IFN gamma non-specifically, and were not therapeutic in adoptive immunotherapy at doses effective for day-7 and day-14 IVS-TDLN cells. In other experiments, IVS cells generated from different lymph node groups in animals bearing 10-day established s.c. tumors were examined and found to have unique profiles of cytokine release. In these studies, the ability of IVS cells to release specifically both cytokines as opposed to one was associated with greater therapeutic efficacy on a per cell basis. Our findings suggest that the tumor-specific releases of GM-CSF and IFN gamma are useful parameters to assess the in vivo therapeutic efficacy of immune lymphocytes.
在本研究中，检测了体外致敏的肿瘤引流淋巴结细胞（IVS-TDLN）释放的细胞因子，并将其与过继性免疫治疗的疗效相关联。在交叉实验中使用了携带免疫特性不同的MCA 207和MCA 205肉瘤肿瘤的小鼠。从携带10天皮下（s.c.）肿瘤的小鼠获得的IVS-TDLN介导了已建立的3天肺转移灶的免疫特异性消退，但在4小时51Cr释放试验中对两种肿瘤均表现出非特异性细胞溶解反应性。相比之下，当用辐照的肿瘤细胞在体外再次刺激时，发现这些IVS-TDLN细胞特异性分泌粒细胞/巨噬细胞集落刺激因子（GM-CSF）和干扰素γ（IFNγ）。为了确定肿瘤特异性细胞因子释放与体内治疗效果的预测价值，对从携带MCA 207肿瘤的动物获得的TDLN在不同时间长度下的抗肿瘤活性进行了动力学分析。来自携带第7、10和14天皮下肿瘤的小鼠的IVS-TDLN细胞表现出GM-CSF和IFNγ的肿瘤特异性释放，并在体内介导了显著的抗肿瘤反应性。相比之下，来自第0天和第21天荷瘤动物的IVS-LN细胞未释放大量的GM-CSF和IFNγ，并且在体内没有治疗效果。第4天的IVS-TDLN非特异性地释放高水平的GM-CSF和IFNγ，并且在对第7天和第14天的IVS-TDLN细胞有效的剂量下，在过继性免疫治疗中没有治疗作用。在其他实验中，检测了从携带10天已建立皮下肿瘤的动物的不同淋巴结组产生的IVS细胞，发现它们具有独特的细胞因子释放谱。在这些研究中，IVS细胞特异性释放两种细胞因子而非一种细胞因子的能力与基于每个细胞的更大治疗效果相关。我们的研究结果表明，GM-CSF和IFNγ的肿瘤特异性释放是评估免疫淋巴细胞体内治疗效果的有用参数。
