Arca M J, Krauss J C, Strome S E, Cameron M J, Chang A E
Department of Surgery, University of Michigan, Ann Arbor 48109, USA.
Cancer Immunol Immunother. 1996 May;42(4):237-45. doi: 10.1007/s002620050276.
We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete interleukin-2 (IL-2), IL-4, interferon gamma (IFN gamma) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFN gamma and IL-4 partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy. Neither IL-2 nor IFN gamma secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not lead to enhanced induction of immune T cells. GM-CSF secretion was found to upregulate B7-1 expression in TDLN, consistent with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T cell immune reactivity to the poorly immunogenic BL6 tumor.
我们评估了对免疫原性较差的B16 - BL6（BL6）小鼠黑色素瘤的体内反应，该黑色素瘤经基因改造后可分泌白细胞介素 - 2（IL - 2）、IL - 4、干扰素γ（IFNγ）和粒细胞/巨噬细胞集落刺激因子（GM - CSF）。评估了三个参数：（1）致瘤性，（2）对未免疫动物的疫苗接种，以及（3）对源自肿瘤引流淋巴结（TDLN）的T细胞抗肿瘤反应性的评估。IL - 2的分泌消除了BL6的致瘤性，而IFNγ和IL - 4部分降低了致瘤性，GM - CSF则无作用。用辐照过的分泌细胞因子的肿瘤进行疫苗接种无法实现对野生型肿瘤攻击的保护性免疫，尽管IL - 2和IL - 4的分泌似乎能显著延缓攻击接种物的生长。评估分泌细胞因子的肿瘤免疫原性的另一种方法是测量从TDLN获得的T细胞在过继免疫治疗中介导野生型肿瘤消退的能力。IL - 2和IFNγ的分泌均未导致免疫T细胞的诱导。相比之下，发现GM - CSF和IL - 4的分泌可在TDLN中诱导免疫T细胞，且GM - CSF优于IL - 4。GM - CSF和IL - 4的联合分泌并未导致免疫T细胞诱导增强。发现GM - CSF的分泌可上调TDLN中B7 - 1的表达，这与抗原呈递细胞群体的增加一致。这些研究表明，细胞因子分泌导致的致瘤性降低与免疫原性增加无关。在所检测的细胞因子中，针对BL6肿瘤产生保护性免疫的能力有限。然而，GM - CSF和IL - 4的分泌显著增强了T细胞对免疫原性较差的BL6肿瘤的免疫反应性。
