Moody D B, Robinson J C, Ewing C M, Lazenby A J, Isaacs W B
Brady Urologic Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Prostate. 1994 May;24(5):244-51. doi: 10.1002/pros.2990240505.
In an effort to stimulate host-mediated antitumor response against prostate cancer in an animal model, highly malignant Dunning MAT-LyLu rat prostate carcinoma cells were transfected with the interleukin-2 (IL-2) cDNA, resulting in their ability to secrete large amounts of biologically active IL-2. Although parental cells form lethal tumors when injected subcutaneously into syngeneic hosts at doses of > or = 5,000, injections of IL-2 secreting cells initially formed tumors and regressed completely in each of over 200 animals at all doses tested (10(4)-8 x 10(7) cells). Mixtures of parental and IL-2 transfected cells were similarly rejected, demonstrating the non-cell autonomous nature of the response. Histological analysis of regressing tumors revealed a vigorous, predominantly lymphocytic and macrophage infiltrate at day 2 and marked tumor necrosis by day 6. Immunohistochemical staining of infiltrating lymphocytes at this latter time point demonstrated numerous T cells bearing either CD4 or CD8 surface markers, suggesting these cells as possibly mediating the tumor rejection. The ability of athymic mice to reject the IL-2 secreting tumor cells, however, suggests a non-T-cell-mediated mechanism. Although splenic natural killer (NK) activity is increased following injection of IL2 secreting tumor cells, this activity appears to be unnecessary for tumor elimination since syngeneic animals injected with asialo-GM1 antiserum to decrease NK activity also rejected IL-2 transfected cells, albeit slightly less effectively than untreated animals. Immunization of animals with subcutaneous injections of IL-2 transfected cells protected animals against a subsequent challenge of 10(4) wild-type cells 1 to 2 weeks later in 19 of 51 cases; however, immunization did not confer protection against larger doses of parental tumor. These studies indicate that high local concentrations of IL-2 stimulate the elimination of large local burdens of prostate cancer in this model system, and this elimination results in a weak, but detectable systemic immune response against wild-type prostate cancer cells.
为了在动物模型中刺激宿主介导的针对前列腺癌的抗肿瘤反应，将高恶性的邓宁MAT-LyLu大鼠前列腺癌细胞用白细胞介素-2（IL-2）cDNA转染，使其能够分泌大量具有生物活性的IL-2。虽然亲代细胞以≥5000的剂量皮下注射到同基因宿主中时会形成致命肿瘤，但注射分泌IL-2的细胞在所有测试剂量（10⁴ - 8×10⁷个细胞）下最初都会形成肿瘤，并在200多只动物中的每一只中完全消退。亲代细胞和IL-2转染细胞的混合物同样被排斥，这表明该反应具有非细胞自主性。对消退肿瘤的组织学分析显示，在第2天有强烈的、主要为淋巴细胞和巨噬细胞浸润，到第6天有明显的肿瘤坏死。在这个后期时间点对浸润淋巴细胞进行免疫组化染色显示，有大量带有CD4或CD8表面标志物的T细胞，表明这些细胞可能介导肿瘤排斥。然而，无胸腺小鼠排斥分泌IL-2的肿瘤细胞的能力表明存在一种非T细胞介导的机制。虽然注射分泌IL-2的肿瘤细胞后脾自然杀伤（NK）活性增加，但这种活性似乎对于肿瘤清除并非必需，因为注射脱唾液酸GM1抗血清以降低NK活性的同基因动物也能排斥IL-2转染细胞，尽管其效果略低于未处理的动物。用皮下注射IL-2转染细胞对动物进行免疫，在51例中有19例在1至2周后能保护动物免受随后10⁴个野生型细胞的攻击；然而，免疫并不能针对更大剂量的亲代肿瘤提供保护。这些研究表明，在该模型系统中，高局部浓度的IL-2刺激消除了大量局部负荷的前列腺癌，并且这种消除导致了针对野生型前列腺癌细胞的微弱但可检测的全身免疫反应。
