PDF(Pubmed)
Abstract：
Epithelial ovarian cancer (OC) stands as one of the deadliest gynecologic malignancies, urgently necessitating novel therapeutic strategies. Approximately 60% of ovarian tumors exhibit reduced expression of major histocompatibility complex class I (MHC I), intensifying immune evasion mechanisms and rendering immunotherapies ineffective. NOD-like receptor CARD domain containing 5 (NLRC5) transcriptionally regulates MHC I genes and many antigen presentation machinery components. We therefore explored the therapeutic potential of NLRC5 in OC.
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.
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.
摘要：
■上皮性卵巢癌（OC）是最致命的妇科恶性肿瘤之一，迫切需要新的治疗策略。大约60%的卵巢肿瘤显示主要组织相容性复合体I类（MHCI）的表达降低，强化免疫逃避机制，使免疫疗法无效。含有NOD样受体CARD结构域的5(NLRC5)转录调节MHCI基因和许多抗原呈递机制组分。因此，我们探索了NLRC5在OC中的治疗潜力。
■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。
■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。
