Immunoendocrinology Lab, National Institute of Immunology, New Delhi, India.
PLoS One. 2013 Apr 8;8(4):e61288. doi: 10.1371/journal.pone.0061288. Print 2013.
Human chorionic gonadotropin (hCG) prolongs the secretion of progesterone from the corpus luteum, providing a critical stimulus for the sustenance of pregnancy. hCG (or individual subunits) is also secreted by a variety of trophoblastic and non-trophoblastic cancers and has been associated with poor prognosis. Early clinical studies have indicated merit in anti-hCG vaccination as potential immunotherapy, but anti-tumor efficacy is believed to be compromised by sub-optimal immunogenecity. In the present study, enhanced tumorigenesis was observed when SP2/O cells were subcutaneously injected in either male or female BALB/c x FVB/J(βhCG/-) F1 transgenic mice, establishing the growth-promoting effects of the gonadotropin for implanted tumors in vivo. The utility of Mycobacterium indicus pranii (MIP) was evaluated, as an innate anti-tumor immunomodulator as well as adjuvant in mice. MIP elicited the secretion of the inflammatory cytokines IFNγ, IL-6, IL-12p40, KC and TNFα from murine antigen presenting cells. When MIP was incorporated into an anti-hCG vaccine formulation previously employed in humans (a βhCG-TT conjugate adsorbed on alum), elevated T cell recall proliferative and cytokine responses to hCG, βhCG and TT were observed. MIP increased vaccine immunogenicity in mice of diverse genetic background (including in traditionally low-responder murine strains), leading to enhanced titres of bioneutralizing anti-hCG antibodies which exhibited cytotoxicity towards tumor cells. Individual administration of MIP and βhCG-TT to BALB/c mice subcutaneously implanted with SP2/O cells resulted in anti-tumor effects; significantly, immunization with βhCG-TT supplemented with MIP invoked synergistic benefits in terms of tumor volume, incidence and survival. The development of novel vaccine formulations stimulating both adaptive and innate anti-tumor immunity to induce collaborative beneficial effects may fill a niche in the adjunct treatment of hCG-sensitive tumors that are resistant to conventional therapy.
人绒毛膜促性腺激素（hCG）延长黄体分泌孕酮，为妊娠提供重要刺激。hCG（或其单个亚基）也由各种滋养层和非滋养层肿瘤分泌，并与不良预后相关。早期临床研究表明，抗 hCG 疫苗接种作为潜在的免疫疗法具有一定价值，但抗肿瘤疗效被认为因免疫原性不理想而受到影响。本研究中，当 SP2/O 细胞被皮下注射到 BALB/c×FVB/J（βhCG/-）F1 转基因雄性或雌性小鼠中时，观察到肿瘤发生增强，这确立了促性腺激素对体内植入肿瘤的促进生长作用。评估了印度分枝杆菌（MIP）的效用，它既是一种先天抗肿瘤免疫调节剂，也是一种佐剂。MIP 可诱导小鼠抗原呈递细胞分泌炎症细胞因子 IFNγ、IL-6、IL-12p40、KC 和 TNFα。当 MIP 被纳入之前在人类中使用的抗 hCG 疫苗制剂（吸附在明矾上的βhCG-TT 缀合物）中时，观察到对 hCG、βhCG 和 TT 的 T 细胞回忆性增殖和细胞因子反应增强。MIP 提高了不同遗传背景（包括传统低反应性小鼠品系）小鼠的疫苗免疫原性，导致针对 hCG 的中和抗体效价增加，这些抗体对肿瘤细胞具有细胞毒性。单独给予 MIP 和βhCG-TT 皮下接种 SP2/O 细胞的 BALB/c 小鼠，可产生抗肿瘤作用；值得注意的是，βhCG-TT 与 MIP 联合免疫可在肿瘤体积、发生率和存活率方面发挥协同作用。开发刺激适应性和先天抗肿瘤免疫的新型疫苗制剂，以诱导协同有益作用，可能在 hCG 敏感肿瘤的辅助治疗中填补一个空白，这些肿瘤对常规治疗具有抗性。
