Yang Y F, Zou J P, Mu J, Wijesuriya R, Ono S, Walunas T, Bluestone J, Fujiwara H, Hamaoka T
Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Cancer Res. 1997 Sep 15;57(18):4036-41.
Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a second counterreceptor for the B7 family of costimulatory molecules, functions as a negative regulator of T-cell activation. Here, we investigated whether the blockade of the CTLA-4 function leads to enhancement of antitumor T-cell responses at various stages of tumor growth. Unfractionated spleen cells taken from CSAIM fibrosarcoma-bearing mice 1-2 weeks after CSA1M cell implantation (early tumor-bearing mice) contained tumor-primed T cells that produced interleukin 2 and IFN-gamma through collaboration with antigen-presenting cell-binding tumor antigens when cultured in vitro. However, this initial lymphokine-producing capacity decreased at later stages of tumor growth (7-10 weeks after tumor cell implantation). Anti-CTLA-4 monoclonal antibody (mAb) was added to whole-spleen cell cultures from early or late tumor-bearing mice. Spleen cells from early tumor-bearing mice exhibited enhanced production of interleukin 2 and IFN-gamma upon in vitro culture in the presence of anti-CTLA-4 mAb. However, addition of anti-CTLA-4 mAb to whole-spleen cell cultures from late tumor-bearing mice failed to display such an enhancement. Consistent with these in vitro results, the in vivo antitumor effect of anti-CTLA-4 administration was observed in a tumor-bearing stage-restricted manner; in vivo administration of anti-CTLA-4 (1 mg/mouse, three times at 1-week intervals) into early tumor-bearing mice resulted in regression of growing tumors, whereas the same treatment did not affect tumor growth when performed for late tumor-bearing mice. Similar anti-CTLA-4 effect was observed in another tumor (OV-HM ovarian carcinoma) model. These in vitro and in vivo results indicate that CTLA-4 blockade in tumor-bearing individuals enhances the capacity to generate antitumor T-cell responses, but the expression of such an enhancing effect is restricted to early stages of tumor growth.
细胞毒性T淋巴细胞相关分子4（CTLA-4）是共刺激分子B7家族的第二个反受体，作为T细胞活化的负调节因子发挥作用。在此，我们研究了CTLA-4功能的阻断是否会在肿瘤生长的各个阶段增强抗肿瘤T细胞反应。在CSA1M细胞植入后1-2周（早期荷瘤小鼠）从携带CSAIM纤维肉瘤的小鼠中获取的未分离脾细胞含有肿瘤致敏T细胞，当在体外培养时，这些T细胞通过与结合肿瘤抗原的抗原呈递细胞协作产生白细胞介素2和干扰素-γ。然而，这种最初产生淋巴因子的能力在肿瘤生长后期（肿瘤细胞植入后7-10周）下降。将抗CTLA-4单克隆抗体（mAb）添加到早期或晚期荷瘤小鼠的全脾细胞培养物中。早期荷瘤小鼠的脾细胞在抗CTLA-4 mAb存在下进行体外培养时，白细胞介素2和干扰素-γ的产生增强。然而，将抗CTLA-4 mAb添加到晚期荷瘤小鼠的全脾细胞培养物中未能显示出这种增强作用。与这些体外结果一致，抗CTLA-4给药的体内抗肿瘤作用以肿瘤负荷阶段受限的方式观察到；向早期荷瘤小鼠体内注射抗CTLA-4（1 mg/小鼠，每隔1周注射3次）导致生长中的肿瘤消退，而对晚期荷瘤小鼠进行相同处理时不影响肿瘤生长。在另一个肿瘤（OV-HM卵巢癌）模型中观察到了类似的抗CTLA-4效应。这些体外和体内结果表明，荷瘤个体中CTLA-4的阻断增强了产生抗肿瘤T细胞反应的能力，但这种增强作用的表达仅限于肿瘤生长的早期阶段。
