Ganesan Priyadarshini L, Alexander Stephen I, Watson Debbie, Logan Grant J, Zhang Geoff Y, Alexander Ian E
Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, NSW, Australia.
Cancer Immunol Immunother. 2007 Dec;56(12):1955-65. doi: 10.1007/s00262-007-0339-7. Epub 2007 Jun 5.
Successful immunotherapy of solid tumors has proven difficult to achieve. The aim of the current study was to further investigate the effects of peripheral CD80-mediated co-stimulation on the efficacy of polyclonal anti-tumor effector CTL in an adoptive transfer model. Splenocytes obtained from wild-type mice immunized with CD80-transduced EL4 tumor cells were expanded in vitro in the presence of either IL-12 or IL-15 and irradiated CD80-transduced EL4 tumor cells. Polyclonal CD8 T cells were the major subset in the effector population. Primed effector cells were adoptively transferred into immuno-deficient Rag-1-deficient mice which were then challenged with syngeneic vector-control or CD80-transduced EL4 tumor cells. Expression of CD80 enhanced the elimination of EL4 tumors and mouse survival. Both IL-12 and IL-15 cultured cells had enhanced cytotoxicity. Importantly, anti-tumor memory was maintained without tumor evasion following re-challenge with either CD80-transduced and vector-control EL4 cells. We also show, using antibody-mediated depletion, that endogenous NK cells present in Rag-1-deficient mice exert anti-EL4 tumor activity that is enhanced by CD80 expression. Collectively these data show that peripheral co-stimulation by tumor expression of CD80 results in enhanced anti-tumor efficacy of NK and polyclonal effector T cells, and suggest that TCR repertoire diversity helps protect against tumor escape and provides memory with resultant robust immunity to subsequent tumor challenge irrespective of CD80 status.
事实证明，实现实体瘤的成功免疫治疗颇具难度。本研究的目的是在过继转移模型中，进一步探究外周CD80介导的共刺激对多克隆抗肿瘤效应性细胞毒性T淋巴细胞（CTL）疗效的影响。从用转导CD80的EL4肿瘤细胞免疫的野生型小鼠中获取脾细胞，在存在IL-12或IL-15以及经辐照的转导CD80的EL4肿瘤细胞的情况下进行体外扩增。多克隆CD8 T细胞是效应细胞群体中的主要亚群。将致敏的效应细胞过继转移到免疫缺陷的Rag-1缺陷小鼠中，然后用同基因载体对照或转导CD80的EL4肿瘤细胞进行攻击。CD80的表达增强了EL4肿瘤的清除及小鼠的存活率。IL-12和IL-15培养的细胞均具有增强的细胞毒性。重要的是，在用转导CD80和载体对照的EL4细胞再次攻击后，抗肿瘤记忆得以维持且未出现肿瘤逃逸。我们还通过抗体介导的清除实验表明，Rag-1缺陷小鼠中存在的内源性自然杀伤（NK）细胞发挥抗EL4肿瘤活性，且该活性因CD80表达而增强。总体而言，这些数据表明肿瘤表达CD80介导的外周共刺激可增强NK细胞和多克隆效应T细胞的抗肿瘤疗效，并提示T细胞受体库的多样性有助于防止肿瘤逃逸，并为后续肿瘤攻击提供记忆，从而产生强大的免疫力，且与CD80状态无关。
