Department of Immunoregulation & Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), 37 SP Mukherjee Road, Kolkata 700026, India.
Immunotherapy. 2011 Aug;3(8):949-69. doi: 10.2217/imt.11.81.
The presence of Tregs in tumors is associated with compromised tumor-specific immune responses and has a clear negative impact on survival of cancer patients. Thus, downregulation of Tregs is considered as a promising cancer immunotherapeutic approach. We have reported previously that neem leaf glycoprotein (NLGP) prophylaxis restricts tumor growth in mice by immune activation. In continuation, here, involvement of NLGP in the modulation of Tregs in association with tumor growth restriction is investigated.
NLGP downregulates CD4+CD25+Foxp3+ Tregs within tumors. NLGP-mediated downregulation of CCR4 along with its ligand CCL22 restricts Treg migration at the tumor site. NLGP is not apoptotic to Tregs but significantly downregulates the expression of Foxp3, CTLA4 and GITR. It also reverses the functional impairment of T-effector cells by Tregs, in terms of IFN-γ secretion, cellular proliferation and tumor cell cytotoxicity. NLGP also facilitates reconditioning of tumor microenvironment (hostile) by increasing IFN-γ and IL-12 but decreasing IL-10, TGF-β, VEGF and IDO, creating an antitumor niche. Interaction between Foxp3, p-NFATc3 and p-Smad2/3, needed for successful Treg function, is also inhibited by NLGP.
All of these coordinated events might result in inhibition of Treg associated-tumor growth and therefore increased survivability of mice having NLGP treatment before or/and after tumor inoculation. Thus, the possibility of NLGP being an excellent tool as a T-cell anergy breaker by abrogating the suppressor functions of Tregs in cancer needs to be explored further in the clinic.
肿瘤中 Tregs 的存在与肿瘤特异性免疫反应受损有关，并且对癌症患者的生存有明显的负面影响。因此，下调 Tregs 被认为是一种有前途的癌症免疫治疗方法。我们之前曾报道过，印度楝叶糖蛋白（NLGP）预防通过免疫激活来限制小鼠的肿瘤生长。在此基础上，本文研究了 NLGP 与肿瘤生长限制相关的 Tregs 调节作用。
NLGP 下调肿瘤内的 CD4+CD25+Foxp3+Tregs。NLGP 介导的 CCR4 及其配体 CCL22 的下调限制了 Treg 在肿瘤部位的迁移。NLGP 对 Tregs 不是凋亡性的，但能显著下调 Foxp3、CTLA4 和 GITR 的表达。它还能逆转 Tregs 对 T 效应细胞的功能障碍，表现在 IFN-γ 分泌、细胞增殖和肿瘤细胞细胞毒性方面。NLGP 还通过增加 IFN-γ 和 IL-12 并降低 IL-10、TGF-β、VEGF 和 IDO 来促进肿瘤微环境（恶劣）的再调节，创造一个抗肿瘤生态位。Foxp3、p-NFATc3 和 p-Smad2/3 之间的相互作用，这是 Treg 功能所必需的，也被 NLGP 抑制。
所有这些协调的事件可能导致 Treg 相关肿瘤生长的抑制，因此，在接种肿瘤之前或之后给予 NLGP 治疗的小鼠的存活率增加。因此，NLGP 通过消除 Tregs 在癌症中的抑制功能作为 T 细胞无能破坏者的可能性需要在临床上进一步探索。
