We generated OC cells overexpressing NLRC5 to rescue MHC I expression and antigen presentation and then assessed their capability to respond to PD-L1 blockade and an infected cell vaccine.
Analysis of microarray datasets revealed a correlation between elevated NLRC5 expression and extended survival in OC patients; however, NLRC5 was scarcely detected in the OC tumor microenvironment. OC cells overexpressing NLRC5 exhibited slower tumor growth and resulted in higher recruitment of leukocytes in the TME with lower CD4/CD8 T-cell ratios and increased activation of T cells. Immune cells from peripheral blood, spleen, and ascites from these mice displayed heightened activation and interferon-gamma production when exposed to autologous tumor-associated antigens. Finally, as a proof of concept, NLRC5 overexpression within an infected cell vaccine platform enhanced responses and prolonged survival in comparison with control groups when challenged with parental tumors.
These findings provide a compelling rationale for utilizing NLRC5 overexpression in \"cold\" tumor models to enhance tumor susceptibility to T-cell recognition and elimination by boosting the presentation of endogenous tumor antigens. This approach holds promise for improving antitumoral immune responses in OC.
■我们产生了过表达NLRC5的OC细胞以挽救MHCI表达和抗原呈递,然后评估了它们对PD-L1阻断和感染的细胞疫苗的反应能力。
对微阵列数据集的分析显示,在OC患者中,NLRC5表达升高与生存期延长之间存在相关性;然而,在OC肿瘤微环境中几乎检测不到NLRC5。过表达NLRC5的OC细胞表现出较慢的肿瘤生长,并导致TME中白细胞的募集增加,CD4/CD8T细胞比率降低,T细胞的活化增加。来自外周血的免疫细胞,脾,脾当暴露于自体肿瘤相关抗原时,这些小鼠的腹水显示出增强的激活和干扰素-γ产生。最后,作为概念的证明,当用亲本肿瘤攻击时,与对照组相比,受感染的细胞疫苗平台内的NLRC5过表达增强应答并延长存活。
■这些发现为在“冷”肿瘤模型中利用NLRC5过表达通过增强内源性肿瘤抗原的呈递来增强肿瘤对T细胞识别和消除的易感性提供了令人信服的理由。这种方法有望改善OC中的抗肿瘤免疫反应。