Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Shimane, Japan.
Cancer Immunol Immunother. 2013 Feb;62(2):383-91. doi: 10.1007/s00262-012-1343-0. Epub 2012 Aug 25.
Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.
几种化疗药物具有免疫调节作用。例如，环磷酰胺（CP）和吉西他滨（GEM）分别通过调节性 T 细胞（Tregs）和髓源性抑制细胞（MDSCs）来减轻免疫抑制。在这里，我们表明，低剂量 CP 加 GEM 的间歇性（节拍式）化疗可诱导 CT26 结肠癌细胞荷瘤小鼠的抗肿瘤 T 细胞免疫。尽管以 8 天间隔注射 CP（100mg/kg）或 4 天间隔注射 CP（50mg/kg）均未观察到明显的生长抑制，但 CP 注射（100mg/kg）增加了引流淋巴结中肿瘤肽特异性 T 淋巴细胞的频率，而两次 4 天间隔注射 CP（50mg/kg）则消除了这种频率。相反，GEM（50mg/kg）注射在体内抑制肿瘤生长的效果优于 GEM（100mg/kg），尽管剂量较小。当 CT26 荷瘤小鼠以 8 天间隔接受低剂量（50mg/kg）CP 加（50mg/kg）GEM 治疗时，肿瘤生长受到抑制而不损害 T 细胞功能；该效果主要依赖于 T 细胞。节拍式联合化疗治愈了三分之一获得肿瘤特异性 T 细胞免疫的 CT26 荷瘤小鼠。联合治疗降低了肿瘤组织中 Foxp3 和精氨酸酶-1 mRNA 水平，但增加了 IFN-γ mRNA 表达。肿瘤浸润性 CD45（+）细胞，特别是 Gr-1（高）CD11b（+）MDSCs 的百分比降低。这些结果表明，低剂量 CP 加 GEM 的节拍式化疗是一种有前途的方案，可以减轻完全由 Treg 和 MDSC 介导的免疫抑制，并在体内引发抗肿瘤 T 细胞免疫。
