Wu Yanhong, Deng Zhenling, Wang Huiru, Ma Wenbo, Zhou Chunxia, Zhang Shuren
Department of Immunology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
Department of Blood Transfusion, Anhui Provincial Hospital, Hefei, People's Republic of China.
BMC Immunol. 2016 Sep 20;17(1):29. doi: 10.1186/s12865-016-0167-7.
Recently, the immunostimulatory roles of chemotherapeutics have been increasingly revealed, although bone marrow suppression is still a common toxicity of chemotherapy. While the numbers and ratios of different immune subpopulations are analyzed after chemotherapy, changes to immune status after each cycle of treatment are less studied and remain unclear.
To determine the tumor-specific immune status and functions after different cycles of chemotherapy, we treated CT26 tumor-bearing mice with one to four cycles of 5-fluorouracil (5-FU). Overall survival was not improved when more than one cycle of 5-FU was administered. Here we present data concerning the immune statuses after one and three cycles of chemotherapy. We analyzed the amount of spleen cells from mice treated with one and three cycles of 5-FU as well as assayed their proliferation and cytotoxicity against the CT26 tumor cell line. We found that the absolute numbers of CD8 T-cells and NK cells were not influenced significantly after either one or three cycles of chemotherapy. However, after three cycles of 5-FU, proliferated CD8 T-cells were decreased, and CT26-specific cytotoxicity and IFN-γ secretion of spleen cells were impaired in vitro. After one cycle of 5-FU, there was a greater percentage of tumor infiltrating CD8 T-cells. In addition, more proliferated CD8 T-cells, enhanced tumor-specific cytotoxicity as well as IFN-γ secretion of spleen cells against CT26 in vitro were observed. Given the increased expression of immunosuppressive factors, such as PD-L1 and TGF-β, we assessed the effect of early introduction of immunotherapy in combination with chemotherapy. We found that mice treated with cytokine induced killer cells and PD-L1 monoclonal antibodies after one cycle of 5-FU had a better anti-tumor performance than those treated with chemotherapy or immunotherapy alone.
These data suggest that a single cycle of 5-FU treatment promoted an anti-tumor immune response, whereas repeated chemotherapy cycles impaired anti-tumor immune functions. Though the amount of immune cells could recover after chemotherapy suspension, their anti-tumor functions were damaged by multiple rounds of chemotherapy. These findings also point towards early implementation of immunotherapy to improve the anti-tumor effect.
近年来，化疗药物的免疫刺激作用日益显现，尽管骨髓抑制仍是化疗常见的毒性反应。在分析化疗后不同免疫亚群的数量和比例时，对每个治疗周期后免疫状态的变化研究较少且仍不清楚。
为了确定不同化疗周期后的肿瘤特异性免疫状态和功能，我们用1至4个周期的5-氟尿嘧啶（5-FU）治疗CT26荷瘤小鼠。给予超过1个周期的5-FU时，总体生存率并未提高。在此，我们展示了关于1个周期和3个周期化疗后免疫状态的数据。我们分析了接受1个周期和3个周期5-FU治疗的小鼠脾脏细胞数量，并检测了它们对CT26肿瘤细胞系的增殖和细胞毒性。我们发现，无论是1个周期还是3个周期的化疗后，CD8 T细胞和NK细胞的绝对数量均未受到显著影响。然而，在3个周期的5-FU治疗后，增殖的CD8 T细胞减少，体外脾脏细胞的CT26特异性细胞毒性和IFN-γ分泌受损。在1个周期的5-FU治疗后，肿瘤浸润CD8 T细胞的百分比更高。此外，体外观察到更多增殖的CD8 T细胞、增强的肿瘤特异性细胞毒性以及脾脏细胞对CT26的IFN-γ分泌。鉴于免疫抑制因子如PD-L1和TGF-β的表达增加，我们评估了早期联合免疫治疗与化疗的效果。我们发现，在1个周期的5-FU治疗后接受细胞因子诱导的杀伤细胞和PD-L1单克隆抗体治疗的小鼠比单独接受化疗或免疫治疗的小鼠具有更好的抗肿瘤性能。
这些数据表明，单周期5-FU治疗可促进抗肿瘤免疫反应，而重复化疗周期会损害抗肿瘤免疫功能。尽管化疗暂停后免疫细胞数量可恢复，但其抗肿瘤功能因多轮化疗而受损。这些发现也表明应尽早实施免疫治疗以提高抗肿瘤效果。
