Paul P. Carbone Comprehensive Cancer Center, Department of Surgery, University of Wisconsin, Madison, WI, USA.
J Immunother. 2011 Jan;34(1):76-84. doi: 10.1097/CJI.0b013e318200b28a.
We have earlier demonstrated T-cell-independent antitumor effects of a combination of anti-CD40 monoclonal antibody (mAb) and CpG oligodeoxynucleotides (CpG) which involved macrophages. As some immunotherapeutic treatments can be potentiated by chemotherapy, we tested if cyclophosphamide (CY) would enhance the antitumor effect of anti-CD40 mAb+CpG. Treatment of B16 melanoma-bearing mice with CY and anti-CD40 mAb+CpG resulted in a significant reduction in tumor growth in immunocompetent mice compared with either CY alone or anti-CD40 mAb with CpG. This enhanced antitumor effect was maintained in severe combined immunodeficiency mice, as measured by both tumor growth and overall survival. Natural killer cells were not required for this antitumor effect as it was also observed in severe combined immunodeficiency/beige mice. Moreover, although CY treatment of immunocompetent mice suppressed natural killer cell activity, it did not negatively affect the antitumor activity of their macrophages when assayed in vitro. Depletion of macrophages in vivo reduced the antitumor effect of CY and anti-CD40 mAb+CpG. These results suggest that therapeutic strategies to activate macrophages may have potential for clinical application in cancer patients receiving chemotherapy.
我们之前已经证明了抗 CD40 单克隆抗体（mAb）和 CpG 寡脱氧核苷酸（CpG）的组合具有非 T 细胞依赖性抗肿瘤作用，这种作用涉及巨噬细胞。由于一些免疫治疗方法可以通过化疗增强，我们测试了环磷酰胺（CY）是否会增强抗 CD40 mAb+CpG 的抗肿瘤作用。与单独使用 CY 或抗 CD40 mAb 联合 CpG 相比，用 CY 和抗 CD40 mAb+CpG 治疗 B16 黑色素瘤荷瘤小鼠导致肿瘤生长显著减少。在严重联合免疫缺陷小鼠中，通过肿瘤生长和总生存期来衡量，这种增强的抗肿瘤作用得以维持。由于在严重联合免疫缺陷/ beige 小鼠中也观察到了这种抗肿瘤作用，因此不需要自然杀伤细胞来发挥这种抗肿瘤作用。此外，尽管 CY 治疗免疫功能正常的小鼠会抑制自然杀伤细胞的活性，但在体外检测时，它不会对其巨噬细胞的抗肿瘤活性产生负面影响。体内耗尽巨噬细胞会降低 CY 和抗 CD40 mAb+CpG 的抗肿瘤作用。这些结果表明，激活巨噬细胞的治疗策略可能有潜力应用于接受化疗的癌症患者。
