Zocchi Maria Raffaella, Costa Delfina, Venè Roberta, Tosetti Francesca, Ferrari Nicoletta, Minghelli Simona, Benelli Roberto, Scabini Stefano, Romairone Emanuele, Catellani Silvia, Profumo Aldo, Poggi Alessandro
Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute , Milan, Italy.
Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST , Genoa, Italy.
Oncoimmunology. 2017 Jan 6;6(3):e1278099. doi: 10.1080/2162402X.2016.1278099. eCollection 2017.
Amino-bis-phosphonates (N-BPs) such as zoledronate (Zol) have been used in anticancer clinical trials due to their ability to upregulate pyrophosphate accumulation promoting antitumor Vγ9Vδ2 T cells. The butyrophilin 3A (BTN3A, CD277) family, mainly the BTN3A1 isoform, has emerged as an important structure contributing to Vγ9Vδ2 T cells stimulation. It has been demonstrated that the B30.2 domain of BTN3A1 can bind phosphoantigens (PAg) and drive the activation of Vγ9Vδ2 T cells through conformational changes of the extracellular domains. Moreover, BTN3A1 binding to the cytoskeleton, and its consequent membrane stabilization, is crucial to stimulate the PAg-induced tumor cell reactivity by human Vγ9Vδ2 T cells. Aim of this study was to investigate the relevance of BTN3A1 in N-BPs-induced antitumor response in colorectal cancer (CRC) and the cell types involved in the tumor microenvironment. In this paper, we show that (i) CRC, exposed to Zol, stimulates the expansion of Vδ2 T lymphocytes with effector memory phenotype and antitumor cytotoxic activity, besides sensitizing cancer cells to γδ T cell-mediated cytotoxicity; (ii) this effect is partially related to BTN3A1 expression and in particular with its cellular re-distribution in the membrane and cytoskeleton-associated fraction; (iii) BTN3A1 is detected in CRC at the tumor site, both on epithelial cells and on tumor-associated fibroblasts (TAF), close to areas infiltrated by Vδ2 T lymphocytes; (iv) Zol is effective in stimulating antitumor effector Vδ2 T cells from CRC cell suspensions; and (v) both CRC cells and TAF can be primed by Zol to trigger Vδ2 T cells.
氨基双膦酸盐（N - BPs）如唑来膦酸（Zol）已用于抗癌临床试验，因为它们能够上调焦磷酸盐积累，从而促进抗肿瘤Vγ9Vδ2 T细胞。嗜乳脂蛋白3A（BTN3A，CD277）家族，主要是BTN3A1异构体，已成为促进Vγ9Vδ2 T细胞刺激的重要结构。已经证明，BTN3A1的B30.2结构域可以结合磷酸抗原（PAg），并通过细胞外结构域的构象变化驱动Vγ9Vδ2 T细胞的激活。此外，BTN3A1与细胞骨架的结合及其随后的膜稳定化，对于刺激人Vγ9Vδ2 T细胞的PAg诱导的肿瘤细胞反应性至关重要。本研究的目的是探讨BTN3A1在结直肠癌（CRC）中N - BPs诱导的抗肿瘤反应中的相关性以及肿瘤微环境中涉及的细胞类型。在本文中，我们表明：（i）暴露于Zol的CRC除了使癌细胞对γδ T细胞介导的细胞毒性敏感外，还刺激具有效应记忆表型和抗肿瘤细胞毒性活性的Vδ2 T淋巴细胞的扩增；（ii）这种效应部分与BTN3A1表达有关，特别是与其在膜和细胞骨架相关部分中的细胞重新分布有关；（iii）在肿瘤部位的CRC中检测到BTN3A1，在上皮细胞和肿瘤相关成纤维细胞（TAF）上均有，靠近Vδ2 T淋巴细胞浸润区域；（iv）Zol可有效刺激CRC细胞悬液中的抗肿瘤效应Vδ2 T细胞；（v）CRC细胞和TAF均可被Zol引发以触发Vδ2 T细胞。
