Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Oregon Health and Science University, Portland, Oregon, USA.
Clin Cancer Res. 2009 Nov 15;15(22):6881-90. doi: 10.1158/1078-0432.CCR-09-1113. Epub 2009 Nov 10.
A single vaccination of intact or reconstituted-lymphopenic mice (RLM) with a granulocyte macrophage colony-stimulating factor-secreting B16BL6-D5 melanoma cell line induces protective antitumor immunity and T cells that mediate the regression of established melanoma in adoptive immunotherapy studies. We wanted to study if multiple vaccinations during immune reconstitution of the lymphopenic host would maintain a potent antitumor immune response.
RLM were vaccinated multiple times over a 40-day period. Spleens were isolated from these mice, activated in vitro, and adoptively transferred into mice bearing 3-day experimental pulmonary metastases.
Multiple vaccinations, rather than boosting the immune response, significantly reduced therapeutic efficacy of adoptive immunotherapy and were associated with an increased frequency and absolute number of CD3+CD4+Foxp3+ T regulatory (T(reg)) cells. Anti-CD4 administration reduced the absolute number of T(reg) cells 9-fold. Effector T-cells generated from anti-CD4-treated mice were significantly (P < 0.0001) more therapeutic in adoptive transfer studies than T cells from multiply vaccinated animals with a full complement of CD4+ cells.
These results suggest that CD4+ T(reg) cells limit the efficacy of multiple vaccinations and that timed partial depletion of CD4+ T cells may reduce suppression and "tip-the-balance" in favor of therapeutic antitumor immunity. The recent failure of large phase III cancer vaccine clinical trials, wherein patients received multiple vaccines, underscores the potential clinical relevance of these findings.
用分泌粒细胞巨噬细胞集落刺激因子的 B16BL6-D5 黑色素瘤细胞系对完整或重建的淋巴细胞减少症小鼠（RLM）进行单次接种，可诱导保护性抗肿瘤免疫和 T 细胞，这些 T 细胞在过继免疫治疗研究中介导已建立的黑色素瘤的消退。我们想研究在淋巴细胞减少症宿主的免疫重建过程中多次接种是否会维持有效的抗肿瘤免疫反应。
RLM 在 40 天的时间内多次接种。从这些小鼠中分离脾脏，在体外激活，并过继转移到 3 天实验性肺转移的小鼠中。
多次接种不仅没有增强免疫反应，反而显著降低了过继免疫治疗的疗效，并与 CD3+CD4+Foxp3+T 调节（Treg）细胞的频率和绝对数量增加有关。抗 CD4 给药将 Treg 细胞的绝对数量减少了 9 倍。从抗 CD4 处理的小鼠中产生的效应 T 细胞在过继转移研究中比来自多次接种动物的 T 细胞更具治疗效果，而多次接种动物的 T 细胞具有完整的 CD4+细胞。
这些结果表明 CD4+Treg 细胞限制了多次接种的疗效，并且 CD4+T 细胞的定时部分耗竭可能会减少抑制作用，并“使天平向有利于治疗性抗肿瘤免疫的方向倾斜”。最近，由于患者接受了多次疫苗接种，大型 III 期癌症疫苗临床试验的失败凸显了这些发现的潜在临床相关性。
