Bracci Laura, Moschella Federica, Sestili Paola, La Sorsa Valentina, Valentini Mara, Canini Irene, Baccarini Sara, Maccari Sonia, Ramoni Carlo, Belardelli Filippo, Proietti Enrico
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):644-53. doi: 10.1158/1078-0432.CCR-06-1209.
Immunotherapy is a promising antitumor strategy, which can be successfully combined with current anticancer treatments, as suggested by recent studies showing the paradoxical chemotherapy-induced enhancement of the immune response. The purpose of the present work is to dissect the biological events induced by chemotherapy that cooperate with immunotherapy in the success of the combined treatment against cancer. In particular, we focused on the following: (a) cyclophosphamide-induced modulation of several cytokines, (b) homeostatic proliferation of adoptively transferred lymphocytes, and (c) homing of transferred lymphocytes to secondary lymphoid organs and tumor mass.
Here, we used the adoptive transfer of tumor-immune cells after cyclophosphamide treatment of tumor-bearing mice as a model to elucidate the mechanisms by which cyclophosphamide can render the immune lymphocytes competent to induce tumor rejection.
The transfer of antitumor immunity was found to be dependent on CD4(+) T cells and on the cooperation of adoptively transferred cells with the host immune system. Of note, tumor-immune lymphocytes migrated specifically to the tumor only in mice pretreated with cyclophosphamide. Cyclophosphamide treatment also promoted homeostatic proliferation/activation of transferred B and T lymphocytes. Optimal therapeutic responses to the transfer of immune cells were associated with the cyclophosphamide-mediated induction of a "cytokine storm" [including granulocyte macrophage colony-stimulating factor, interleukin (IL)-1beta, IL-7, IL-15, IL-2, IL-21, and IFN-gamma], occurring during the "rebound phase" after drug-induced lymphodepletion.
The ensemble of these data provides a new rationale for combining immunotherapy and chemotherapy to induce an effective antitumor response in cancer patients.
免疫疗法是一种很有前景的抗肿瘤策略，近期研究表明化疗可反常地诱导免疫反应增强，这表明免疫疗法能成功地与当前的抗癌治疗方法相结合。本研究的目的是剖析化疗诱导的生物学事件，这些事件在联合抗癌治疗的成功中与免疫疗法协同作用。具体而言，我们聚焦于以下几点：（a）环磷酰胺对多种细胞因子的调节作用；（b）过继转移淋巴细胞的稳态增殖；（c）转移的淋巴细胞归巢至次级淋巴器官和肿瘤块。
在此，我们以环磷酰胺处理荷瘤小鼠后过继转移肿瘤免疫细胞为模型，以阐明环磷酰胺使免疫淋巴细胞能够诱导肿瘤排斥的机制。
发现抗肿瘤免疫的转移依赖于CD4(+) T细胞以及过继转移细胞与宿主免疫系统的协同作用。值得注意的是，只有在经环磷酰胺预处理的小鼠中，肿瘤免疫淋巴细胞才会特异性迁移至肿瘤。环磷酰胺处理还促进了转移的B和T淋巴细胞的稳态增殖/活化。对免疫细胞转移的最佳治疗反应与环磷酰胺介导的“细胞因子风暴”（包括粒细胞巨噬细胞集落刺激因子、白细胞介素（IL）-1β、IL-7、IL-15、IL-2、IL-21和IFN-γ）的诱导有关，该“细胞因子风暴”发生在药物诱导的淋巴细胞减少后的“反弹期”。
这些数据共同为免疫疗法和化疗联合应用以在癌症患者中诱导有效的抗肿瘤反应提供了新的理论依据。
