Dipartimento di Discipline Chirurgiche ed Anatomiche, Università di Palermo, Palermo, Italy.
PLoS One. 2013 Jun 6;8(6):e65145. doi: 10.1371/journal.pone.0065145. Print 2013.
Colon cancer comprises a small population of cancer initiating stem cells (CIC) that is responsible for tumor maintenance and resistance to anti-cancer therapies, possibly allowing for tumor recapitulation once treatment stops. Combinations of immune-based therapies with chemotherapy and other anti-tumor agents may be of significant clinical benefit in the treatment of colon cancer. However, cellular immune-based therapies have not been experimented yet in the population of colon CICs. Here, we demonstrate that treatment with low concentrations of commonly used chemotherapeutic agents, 5-fluorouracyl and doxorubicin, sensitize colon CICs to Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell cytotoxicity was largely mediated by TRAIL interaction with DR5, following NKG2D-dependent recognition of colon CIC targets. We conclude that in vivo activation of Vγ9Vδ2 T cells or adoptive administration of ex-vivo expanded Vγ9Vδ2 T cells at suitable intervals after chemotherapy may substantially increase anti-tumor activities and represent a novel strategy for colon cancer immunotherapy.
结直肠癌包含一小部分癌症起始干细胞（CIC），这些细胞负责肿瘤的维持和对癌症治疗的抵抗，这可能导致治疗停止后肿瘤的再次发生。将免疫疗法与化疗和其他抗肿瘤药物联合使用，可能会对结直肠癌的治疗有显著的临床获益。然而，细胞免疫疗法尚未在结直肠 CIC 人群中进行实验。在这里，我们证明，低浓度的常用化疗药物 5-氟尿嘧啶和阿霉素处理可使结肠 CIC 对 Vγ9Vδ2 T 细胞细胞毒性敏感。Vγ9Vδ2 T 细胞的细胞毒性主要通过 TRAIL 与 DR5 的相互作用介导，随后通过 NKG2D 依赖的方式识别结肠 CIC 靶标。我们得出结论，在化疗后合适的时间间隔内体内激活 Vγ9Vδ2 T 细胞或过继给予体外扩增的 Vγ9Vδ2 T 细胞，可能会大大增强抗肿瘤活性，并为结直肠癌的免疫治疗提供一种新策略。
