Capobianco Annalisa, Manfredi Angelo A, Monno Antonella, Rovere-Querini Patrizia, Rugarli Claudio
Department of Oncology, Cancer Immunotherapy and Gene Therapy Program, Clinical Immunology Unit, H San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milano, Italy.
J Immunother. 2008 Jun;31(5):458-65. doi: 10.1097/CJI.0b013e318174a512.
Dendritic cells (DCs) are promising tools for tumor immunotherapy. Their efficacy in the tumor environment increases when tumor cells die as a consequence of chemo/radiotherapy or when local stimuli promoting DC maturation and function are available. Dying tumor cells could represent a source of tumor antigens, which DCs cross-present to tumor-specific T cells. The outcome of cross presentation is in turn determined by the maturation state of DCs. Natural killer (NK)/lymphokine-activated killer (LAK) cells injected into growing tumors could both provide a source of dying cells for cross-presentation and deliver stimuli for DC maturation. Here, we report that NK/LAK cells recognized and killed in vivo major histocompatibility complex class I(low) highly tumorigenic, nonimmunogenic B16F1 melanoma cells when injected into exponentially growing neoplastic lesions. The simultaneous injection of immature DCs was required to heal animals. Similar results were obtained injecting NK/LAK cells and DC into growing Raucher leukaemia virus induced cell line lymphomas. Cured mice failed to reject other implantable tumors, and developed a specific cytotoxic response against the original neoplasm; moreover, they developed a long-lasting memory, and were protected against further challenges with living tumor cells only when both cell populations were introduced. The response associated to the preferential recruitment within tumors of eosinophils. The simultaneous injection in solid tumors of DCs and NK/LAK cells represents an attractive approach for antineoplastic immunotherapeutic strategies.
树突状细胞（DCs）是肿瘤免疫治疗中很有前景的工具。当肿瘤细胞因化疗/放疗而死亡，或者存在促进DC成熟和功能的局部刺激时，它们在肿瘤环境中的疗效会增加。垂死的肿瘤细胞可能是肿瘤抗原的来源，DCs将其交叉呈递给肿瘤特异性T细胞。交叉呈递的结果又由DCs的成熟状态决定。注入生长中的肿瘤的自然杀伤（NK）/淋巴因子激活的杀伤（LAK）细胞既可以为交叉呈递提供垂死细胞的来源，又可以为DC成熟提供刺激。在这里，我们报告，当注入指数生长的肿瘤性病变时，NK/LAK细胞在体内识别并杀死了主要组织相容性复合体I类（低）的高致瘤性、非免疫原性B16F1黑色素瘤细胞。需要同时注入未成熟的DCs才能治愈动物。将NK/LAK细胞和DC注入生长中的劳氏白血病病毒诱导的细胞系淋巴瘤中也获得了类似的结果。治愈的小鼠未能排斥其他可植入肿瘤，并对原始肿瘤产生了特异性细胞毒性反应；此外，它们产生了持久的记忆，并且只有在同时引入两种细胞群体时才受到保护，免受活肿瘤细胞的进一步攻击。该反应与嗜酸性粒细胞在肿瘤内的优先募集有关。在实体瘤中同时注入DCs和NK/LAK细胞是抗肿瘤免疫治疗策略的一种有吸引力的方法。
