Banerjee Saptak, Ghosh Tithi, Barik Subhasis, Das Arnab, Ghosh Sarbari, Bhuniya Avishek, Bose Anamika, Baral Rathindranath
Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), Kolkata, India.
PLoS One. 2014 Nov 12;9(11):e110040. doi: 10.1371/journal.pone.0110040. eCollection 2014.
We have reported that prophylactic as well as therapeutic administration of neem leaf glycoprotein (NLGP) induces significant restriction of solid tumor growth in mice. Here, we investigate whether the effect of such pretreatment (25µg/mice; weekly, 4 times) benefits regulation of tumor angiogenesis, an obligate factor for tumor progression. We show that NLGP pretreatment results in vascular normalization in melanoma and carcinoma bearing mice along with downregulation of CD31, VEGF and VEGFR2. NLGP pretreatment facilitates profound infiltration of CD8+ T cells within tumor parenchyma, which subsequently regulates VEGF-VEGFR2 signaling in CD31+ vascular endothelial cells to prevent aberrant neovascularization. Pericyte stabilization, VEGF dependent inhibition of VEC proliferation and subsequent vascular normalization are also experienced. Studies in immune compromised mice confirmed that these vascular and intratumoral changes in angiogenic profile are dependent upon active adoptive immunity particularly those mediated by CD8+ T cells. Accumulated evidences suggest that NLGP regulated immunomodulation is active in tumor growth restriction and normalization of tumor angiogenesis as well, thereby, signifying its clinical translation.
我们曾报道,印楝叶糖蛋白(NLGP)的预防性和治疗性给药均能显著抑制小鼠实体瘤的生长。在此,我们研究这种预处理(25μg/小鼠;每周一次,共4次)的效果是否有利于调节肿瘤血管生成,肿瘤血管生成是肿瘤进展的一个必要因素。我们发现,NLGP预处理可使荷黑素瘤和荷癌小鼠的血管正常化,同时下调CD31、VEGF和VEGFR2。NLGP预处理促进CD8+T细胞在肿瘤实质内的大量浸润,随后调节CD31+血管内皮细胞中的VEGF-VEGFR2信号传导,以防止异常的新生血管形成。还观察到周细胞稳定、VEGF依赖性抑制血管内皮细胞增殖以及随后的血管正常化。对免疫受损小鼠的研究证实,血管生成谱中的这些血管和肿瘤内变化依赖于主动过继免疫,尤其是由CD8+T细胞介导的免疫。越来越多的证据表明,NLGP调节的免疫调节在肿瘤生长限制和肿瘤血管生成正常化方面也具有活性,从而表明其具有临床转化价值。