Tumor immunogenicity regulates host immune responses, and conventional dendritic cell type 2 uptakes the majority of tumor antigens in an orthotopic lung cancer model.

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-10-03 DOI:10.1007/s00262-024-03828-w
Ki-Hyun Kim, Seung-Jae Kim, Jacob D Eccles, Christian Ascoli, Gye Young Park
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Abstract

Human lung cancer carries high genetic alterations, expressing high tumor-specific neoantigens. Although orthotopic murine lung cancer models recapitulate many characteristics of human lung cancers, genetically engineered mouse models have fewer somatic mutations than human lung cancer, resulting in scarce immune cell infiltration and deficient immune responses. The endogenous mouse lung cancer model driven by Kras mutation and Trp53 deletion (KP model) has minimal immune infiltration because of a scarcity of neoantigens. Fine-tuning tumor antigenicity to trigger the appropriate level of antitumor immunity would be key to investigating immune responses against human lung cancer. We engineered the KP model to express antigens of OVA peptides (minOVA) as neoantigens along with ZsGreen, a traceable fluorescent conjugate. The KP model expressing minOVA exhibited stronger immunogenicity with higher immune cell infiltration comprised of CD8+ T cells and CD11c+ dendritic cells (DCs). Consequently, the KP model expressing minOVA exhibits suppressed tumor growth compared to its origin. We further analyzed tumor-infiltrated DCs. The majority of ZsGreen conjugated with minOVA was observed in the conventional type 2 DCs (cDC2), whereas cDC1 has minimal. These data indicate that tumor immunogenicity regulates host immune responses, and tumor neoantigen is mostly recognized by cDC2 cells, which may play a critical role in initiating antitumor immune responses in an orthotopic murine lung cancer model.

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肿瘤的免疫原性调节宿主的免疫反应,传统的树突状细胞 2 型在正位肺癌模型中吸收了大部分肿瘤抗原。
人类肺癌具有高度基因改变,表达大量肿瘤特异性新抗原。虽然正位小鼠肺癌模型再现了人类肺癌的许多特征,但基因工程小鼠模型的体细胞突变少于人类肺癌,导致免疫细胞浸润稀少和免疫反应不足。由 Kras 突变和 Trp53 缺失驱动的内源性小鼠肺癌模型(KP 模型)由于缺乏新抗原,免疫浸润极少。微调肿瘤抗原性以触发适当水平的抗肿瘤免疫是研究人类肺癌免疫反应的关键。我们设计了 KP 模型,以表达作为新抗原的 OVA 肽抗原(minOVA)和 ZsGreen(一种可追踪的荧光共轭物)。表达 minOVA 的 KP 模型表现出更强的免疫原性和更高的免疫细胞浸润,其中包括 CD8+ T 细胞和 CD11c+ 树突状细胞(DC)。因此,表达 minOVA 的 KP 模型的肿瘤生长比其原发模型受到抑制。我们进一步分析了肿瘤浸润的 DCs。在传统的 2 型 DCs(cDC2)中观察到了大部分与 minOVA 结合的 ZsGreen,而 cDC1 中的 ZsGreen 极少。这些数据表明,肿瘤免疫原性调控宿主免疫反应,肿瘤新抗原主要由 cDC2 细胞识别,它们可能在正位小鼠肺癌模型中启动抗肿瘤免疫反应中发挥关键作用。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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