过继转移的CD8 + T细胞在肿瘤部位的快速积累与SV40 T抗原诱导肿瘤的长期控制相关。
Rapid accumulation of adoptively transferred CD8+ T cells at the tumor site is associated with long-term control of SV40 T antigen-induced tumors.
作者信息
Yorty Jodi L, Tevethia Satvir S, Schell Todd D
机构信息
Department of Microbiology and Immunology, H107, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
出版信息
Cancer Immunol Immunother. 2008 Jun;57(6):883-95. doi: 10.1007/s00262-007-0424-y. Epub 2007 Nov 15.
We previously established a model to study CD8(+) T cell (T(CD8))-based adoptive immunotherapy of cancer using line SV11 mice that develop choroid plexus tumors in the brain due to transgenic expression of Simian Virus 40 large T antigen (Tag). These mice are tolerant to the three dominant T(CD8)-recognized Tag epitopes I, II/III and IV. However, adoptive transfer of spleen cells from naïve C57BL/6 (B6) mice prolongs SV11 survival following T(CD8) priming against the endogenous Tag epitope IV. In addition, survival of SV11 mice is dramatically increased following transfer of lymphocytes from Tag-immune B6 mice. In the current study, we compared the kinetics and magnitude of Tag-specific T(CD8) accumulation at the tumor site following adoptive transfer with a high dose of either Tag-immune or naïve donor cells or decreasing doses of Tag-immune lymphocytes. Following adoptive transfer of Tag-immune cells, epitope I- and IV-specific T(CD8) accumulated to high levels in the brain of SV11 mice, peaking at 5-7 days, while epitope IV-specific T(CD8 )derived from naïve donors required three weeks to achieve peak levels. A similar delay in the peak of epitope IV-specific T(CD8) accumulation was observed when tenfold fewer Tag-immune donor cells were administered, reducing control of tumor progression. These results suggest that efficient and prolonged control of established autochthonous tumors is associated with high-level early accumulation of adoptively transferred T cells. We also provide evidence that although multiple specificities are represented in the Tag immune donor lymphocytes, epitope IV-specific donor T(CD8) play a predominant role in control of tumor growth.
我们之前建立了一个模型,用于研究基于CD8(+) T细胞(T(CD8))的癌症过继性免疫疗法,该模型使用的是SV11品系小鼠,由于猿猴病毒40大T抗原(Tag)的转基因表达,这些小鼠会在大脑中发生脉络丛肿瘤。这些小鼠对三种主要的T(CD8)识别的Tag表位I、II/III和IV具有耐受性。然而,在用针对内源性Tag表位IV进行T(CD8)致敏后,将来自未致敏的C57BL/6(B6)小鼠的脾细胞进行过继性转移,可延长SV11小鼠的生存期。此外,在转移来自Tag免疫的B6小鼠的淋巴细胞后,SV11小鼠的生存期显著延长。在本研究中,我们比较了过继性转移高剂量的Tag免疫或未致敏供体细胞或逐渐减少剂量的Tag免疫淋巴细胞后,肿瘤部位Tag特异性T(CD8)积累的动力学和幅度。在过继性转移Tag免疫细胞后,表位I和IV特异性T(CD8)在SV11小鼠大脑中积累至高水平,在5 - 7天达到峰值,而来自未致敏供体的表位IV特异性T(CD8)需要三周时间才能达到峰值水平。当给予的Tag免疫供体细胞数量减少十倍时,观察到表位IV特异性T(CD8)积累峰值出现类似延迟,从而降低了对肿瘤进展的控制。这些结果表明,对已建立的原发性肿瘤进行有效和持久的控制与过继性转移T细胞的高水平早期积累有关。我们还提供了证据表明,尽管Tag免疫供体淋巴细胞中存在多种特异性,但表位IV特异性供体T(CD8)在控制肿瘤生长中起主要作用。