Natural killer (NK) cells are key components of the immune response to viral infections and cancer. Their functions are controlled by activating and inhibitory killer-cell immunoglobulin-like receptors (KIR) which have MHC class I ligands. KIR2DS2 is an activating KIR, that binds conserved viral peptides in the context of HLA-C and has been associated with protective responses to both cancer and viral infections. We sought to investigate whether NK cells can be specifically activated in a peptide:MHC dependent manner to generate functional immune responses as a potential immunotherapeutic strategy. We developed a peptide-based KIR targeting DNA vaccine. Immunizing KIR-Tg mice with the vaccine construct generated in vivo peptide-specific activation of KIR2DS2-positive NK cells leading to canonical and cross-reactive peptide specific immune responses in vitro, and also in vivo inhibition of tumor growth. Using immunopeptidomics we identified that the nuclear export protein XPO1, which has been associated with a poor prognosis in many different human cancers, furnishes an HLA-C restricted cancer-associated peptide ligand for KIR2DS2-positive NK cells. We thus define a novel strategy to activate KIR in a peptide-specific manner and identify a rationale for its use in cancer immunotherapy.

中文翻译：

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肽：MHC依赖的通过KIR2DS2激活的自然杀伤细胞产生抗肿瘤反应

天然杀伤（NK）细胞是对病毒感染和癌症的免疫反应的关键组成部分。它们的功能受具有MHC I类配体的活化和抑制性杀伤细胞免疫球蛋白样受体（KIR）的控制。KIR2DS2是一种活化的KIR，在HLA-C的背景下与保守的病毒肽结合，并且已与针对癌症和病毒感染的保护性反应相关。我们试图研究是否可以以依赖肽：MHC的方式特异性激活NK细胞，以产生功能性免疫应答作为潜在的免疫治疗策略。我们开发了一种基于肽的KIR靶向DNA疫苗。用疫苗构建体免疫KIR-Tg小鼠会在体内产生KIR2DS2阳性NK细胞的肽特异性激活，从而导致体外的规范性和交叉反应性肽特异性免疫反应，并在体内抑制肿瘤的生长。使用免疫肽组学，我们发现核输出蛋白XPO1与许多不同的人类癌症的预后不良相关，为KIR2DS2阳性NK细胞提供了HLA-C限制的癌症相关肽配体。因此，我们定义了一种以肽特异性方式激活KIR的新策略，并确定了其在癌症免疫治疗中的基本原理。为KIR2DS2阳性NK细胞提供一种HLA-C限制的癌症相关肽配体。因此，我们定义了一种以肽特异性方式激活KIR的新策略，并确定了其在癌症免疫治疗中的基本原理。为KIR2DS2阳性NK细胞提供一种HLA-C限制的癌症相关肽配体。因此，我们定义了一种以肽特异性方式激活KIR的新策略，并确定了其在癌症免疫治疗中的基本原理。