Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India.
Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, India.
FASEB J. 2022 May;36(5):e22268. doi: 10.1096/fj.202101093R.
Altered RGS5-associated intracellular pericyte signaling and its abnormal crosstalk with endothelial cells (ECs) result chaotic tumor-vasculature, prevent effective drug delivery, promote immune-evasion and many more to ensure ultimate tumor progression. Moreover, the frequency of lethal-RGS5 pericytes within tumor was found to increase with disease progression, which signifies the presence of altered cell death pathway within tumor microenvironment (TME). In this study, we checked whether and how neem leaf glycoprotein (NLGP)-immunotherapy-mediated tumor growth restriction is associated with modification of pericytes' signaling, functions and its interaction with ECs. Analysis of pericytes isolated from tumors of NLGP treated mice suggested that NLGP treatment promotes apoptosis of NG2 RGS5 -fuctionally altered pericytes by downregulating intra-tumoral TGFβ, along with maintenance of more matured RGS5 pericytes. NLGP-mediated inhibition of TGFβ within TME rescues binding of RGS5 with Gαi and thereby termination of PI3K-AKT mediated survival signaling by downregulating Bcl2 and initiating pJNK mediated apoptosis. Limited availability of TGFβ also prevents complex-formation between RGS5 and Smad2 and rapid RGS5 nuclear translocation to mitigate alternate immunoregulatory functions of RGS5 tumor-pericytes. We also observed binding of Ang1 from pericytes with Tie2 on ECs in NLGP-treated tumor, which support re-association of pericytes with endothelium and subsequent vessel stabilization. Furthermore, NLGP-therapy- associated RGS5 deficiency relieved CD4 and CD8 T cells from anergy by regulating 'alternate-APC-like' immunomodulatory characters of tumor-pericytes. Taken together, present study described the mechanisms of NLGP's effectiveness in normalizing tumor-vasculature by chiefly modulating pericyte-biology and EC-pericyte interactions in tumor-host to further strengthen its translational potential as single modality treatment.
改变的 RGS5 相关的周细胞内信号及其与内皮细胞（ECs）的异常串扰导致肿瘤血管混乱，阻止了有效的药物输送，促进了免疫逃逸等等，以确保肿瘤的最终进展。此外，研究发现肿瘤中致命性 RGS5 周细胞的频率随着疾病的进展而增加，这表明肿瘤微环境（TME）中存在改变的细胞死亡途径。在这项研究中，我们检查了是否以及如何通过 Neem 叶糖蛋白（NLGP）免疫疗法介导的肿瘤生长限制与周细胞信号的改变、功能及其与 ECs 的相互作用有关。对来自 NLGP 治疗小鼠肿瘤中分离的周细胞的分析表明，NLGP 治疗通过下调肿瘤内 TGFβ，促进 NG2 RGS5 功能改变的周细胞凋亡，同时维持更成熟的 RGS5 周细胞。NLGP 介导的 TME 内 TGFβ 的抑制作用挽救了 RGS5 与 Gαi 的结合，从而通过下调 Bcl2 并启动 pJNK 介导的凋亡来终止 PI3K-AKT 介导的存活信号。TGFβ 的有限可用性也阻止了 RGS5 与 Smad2 之间的复合物形成，并迅速使 RGS5 核转位，以减轻 RGS5 肿瘤周细胞的替代免疫调节功能。我们还观察到 NLGP 处理的肿瘤中周细胞的 Ang1 与 EC 上的 Tie2 结合，这支持周细胞与内皮细胞的重新结合以及随后的血管稳定。此外，NLGP 治疗相关的 RGS5 缺乏通过调节肿瘤周细胞的“替代 APC 样”免疫调节特性，使 CD4 和 CD8 T 细胞免于无能。综上所述，本研究描述了 NLGP 通过主要调节肿瘤宿主中的周细胞生物学和 EC-周细胞相互作用来使肿瘤血管正常化的机制，进一步增强了其作为单一治疗模式的转化潜力。
