Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo
Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo
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DOI：
10.1007/s00262-012-1343-0
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发表时间：
2013-02-01
影响因子：
5.8
通讯作者：
Harada, Mamoru
中科院分区：
文献类型：
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作者：
Tongu, Miki;Harashima, Nanae;Harada, Mamoru
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）分别减少调节性T细胞（TCFs）和髓源性抑制细胞（MDSC）的免疫抑制。在这里，我们表明，间歇（节拍）化疗与低剂量CP加GEM可以诱导抗肿瘤T细胞免疫CT 26结肠癌荷瘤小鼠。虽然没有观察到显着的生长抑制注射CP（100 mg/kg）在8天的时间间隔或CP（50 mg/kg）在4天的时间间隔，CP注射（100 mg/kg）增加引流淋巴结中的肿瘤肽特异性T淋巴细胞的频率，这是取消了两次注射CP（50 mg/kg）在4天的时间间隔。或者，注射GEM（50 mg/kg）在体内抑制肿瘤生长方面上级GEM（100 mg/kg），尽管剂量较小。当CT 26荷瘤小鼠以8天间隔接受低剂量（50 mg/kg）CP加（50 mg/kg）GEM治疗时，肿瘤生长受到抑制，而不损害T细胞功能;该效应主要是T细胞依赖性的。节拍联合化疗治愈了三分之一获得肿瘤特异性T细胞免疫的CT 26荷瘤小鼠。联合治疗降低了肿瘤组织中Foxp 3和IFN-γ酶-1 mRNA水平，但增加了IFN-γ mRNA表达。肿瘤浸润的CD 45（+）细胞，尤其是Gr-1（高）CD 11b（+）MDSC的百分比降低。这些结果表明，节拍化疗与低剂量CP加GEM是一个有前途的协议，以减轻完全Treg和MDSC介导的免疫抑制，并在体内引发抗肿瘤T细胞免疫。
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-gamma 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.