Abrams S I, Hodge J W, McLaughlin J P, Steinberg S M, Kantor J A, Schlom J
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1750, USA.
J Immunother. 1997 Jan;20(1):48-59. doi: 10.1097/00002371-199701000-00005.
We have described previously the construction, generation, and in vivo biologic consequences of a recombinant vaccinia virus containing the human CEA gene (rV-CEA) in an experimental murine colon carcinoma model. Immunization of C57BL/6 mice with rV-CEA led to antigen-specific inhibition of tumor growth in both prophylactic and therapeutic settings. Although such antitumor effects were correlated with the induction of CEA-specific T-cell responses, their exact contribution in the tumor rejection mechanism remained unclear. In this study, we examined the mechanism of action of rV-CEA, with emphasis on definition of the immune cells important for such antitumor effects. To that end, a cellular adoptive transfer model was established in vivo, which allowed specific functional analysis of donor-derived immune cells in naive, sublethally irradiated, tumor-bearing recipients. Splenocytes from rV-CEA-immunized donors expressed strong antitumor activity in such tumor-bearing recipients, whereas nonimmune donor cells did not. Depletion of immune T cells before cellular transfer abolished the antitumor response. Moreover, depletion of CD8+ T cells before transfer resulted in the loss of antitumor activity, despite the presence of CD4+ T cells. In contrast, antitumor activity was demonstrable with CD8-containing, CD4-depleted effectors, although it was not as effective as with both T-cell subpopulations combined. Finally, in beta 2-microglobulin/CD8+ T-cell-deficient mice, rV-CEA immunization exerted only partial antitumor protection, compared with the immune-competent controls. Overall, we demonstrated that (a) antitumor activity induced by rV-CEA was essentially mediated by CD8+ effectors; and (b) the combination of both CD8+ and CD4+ lymphocytes led to maximal antitumor therapeutic effects, suggesting an important helper or immunoregulatory contribution of the CD4+ subset. Thus, adoptive cellular transfer strategies may have implications for both the study of recombinant anticancer vaccines and the development of potential clinical applications for cancer immunotherapy.
我们之前已经描述了一种含有人类癌胚抗原基因的重组痘苗病毒（rV-CEA）在实验性小鼠结肠癌模型中的构建、产生及其体内生物学效应。用rV-CEA免疫C57BL/6小鼠在预防和治疗两种情况下均导致肿瘤生长的抗原特异性抑制。尽管这种抗肿瘤作用与癌胚抗原特异性T细胞反应的诱导相关，但其在肿瘤排斥机制中的确切作用仍不清楚。在本研究中，我们研究了rV-CEA的作用机制，重点是确定对这种抗肿瘤作用重要的免疫细胞。为此，在体内建立了细胞过继转移模型，该模型允许对未受照射、接受亚致死剂量照射且荷瘤的受体中供体来源的免疫细胞进行特异性功能分析。来自rV-CEA免疫供体的脾细胞在此类荷瘤受体中表现出强大的抗肿瘤活性，而未免疫的供体细胞则没有。细胞转移前免疫T细胞的耗竭消除了抗肿瘤反应。此外，转移前CD8+ T细胞的耗竭导致抗肿瘤活性丧失，尽管存在CD4+ T细胞。相比之下，含有CD8、去除CD4的效应细胞具有抗肿瘤活性，尽管其效果不如两种T细胞亚群联合使用时有效。最后，在β2-微球蛋白/CD8+ T细胞缺陷小鼠中，与免疫功能正常的对照相比，rV-CEA免疫仅发挥了部分抗肿瘤保护作用。总体而言，我们证明：（a）rV-CEA诱导的抗肿瘤活性主要由CD8+效应细胞介导；（b）CD8+和CD4+淋巴细胞的联合导致最大的抗肿瘤治疗效果，表明CD4+亚群具有重要的辅助或免疫调节作用。因此，细胞过继转移策略可能对重组抗癌疫苗的研究以及癌症免疫治疗潜在临床应用的开发都具有重要意义。
