Levy Moshe Yair, Sidana Abhinav, Chowdhury Wasim H, Solomon Steven B, Drake Charles G, Rodriguez Ronald, Fuchs Ephraim J
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 2009 Aug;330(2):596-601. doi: 10.1124/jpet.109.152603. Epub 2009 Apr 30.
Cryoablation of a solitary tumor mass releases intact tumor antigens and can induce protective antitumor immunity but has limited efficacy in the treatment of established metastatic cancer. Cyclophosphamide (Cy), an anticancer drug, selectively depletes regulatory T cells (T(reg)s) and attenuates suppression of antitumor immunity. We used a BALB/c mouse model of metastatic colon cancer to investigate the systemic antitumor effects of in situ cryotherapy alone or in combination with 200 mg/kg i.p. Cy. When combined with Cy, cryoablation was significantly more effective than either surgical excision or cautery at inducing systemic antitumor immunity, resulting in the cure of a fraction of animals with established metastatic disease and resistance to tumor rechallenge. Lymphocytes from cured animals contained an expanded population of tumor-specific, interferon-gamma producing T cells and transferred antitumor immunity to naive recipients. Depletion of CD8(+) cells significantly impaired the adoptive transfer of antitumor immunity. Furthermore, treatment with Cy and cryoablation was associated with a significant decrease in the ratio of regulatory to effector CD4(+) T cells. The combination of tumor cryoablation and Cy induces potent, systemic antitumor immunity in animals with established metastatic disease.
孤立肿瘤块的冷冻消融可释放完整的肿瘤抗原并能诱导保护性抗肿瘤免疫，但在治疗已形成的转移性癌症方面疗效有限。环磷酰胺（Cy）是一种抗癌药物，可选择性地耗竭调节性T细胞（Tregs）并减弱对抗肿瘤免疫的抑制作用。我们使用转移性结肠癌的BALB/c小鼠模型来研究单独原位冷冻疗法或与200mg/kg腹腔注射Cy联合应用的全身抗肿瘤作用。当与Cy联合使用时，冷冻消融在诱导全身抗肿瘤免疫方面比手术切除或烧灼显著更有效，导致一部分患有已形成转移性疾病的动物治愈并对肿瘤再次攻击产生抗性。治愈动物的淋巴细胞含有一群扩增的肿瘤特异性、产生干扰素-γ的T细胞，并将抗肿瘤免疫转移给未接触过抗原的受体。CD8(+)细胞的耗竭显著损害了抗肿瘤免疫的过继转移。此外，Cy和冷冻消融治疗与调节性CD4(+)T细胞与效应性CD4(+)T细胞的比例显著降低有关。肿瘤冷冻消融和Cy的联合应用可在患有已形成转移性疾病的动物中诱导强大的全身抗肿瘤免疫。
