Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC.
Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC.
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DOI：
10.3389/fcell.2022.816517
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发表时间：
2022
影响因子：
5.5
通讯作者：
Barry ST
中科院分区：
文献类型：
--
作者：
Cattolico C;Bailey P;Barry ST
免疫疗法彻底改变了许多癌症类型的治疗。然而，胰腺导管腺癌（PDAC）对免疫检查点抑制剂的反应较差，基于免疫治疗的试验没有产生令人信服的临床活性。PDAC肿瘤通常具有低的肿瘤CD 8 + T细胞浸润和高度免疫抑制的微环境。这些特征将PDAC分类为免疫学上的“冷”。然而，肿瘤T细胞的存在是PDAC中有利的预后特征。内在的肿瘤细胞特性控制与免疫系统的相互作用。肿瘤DNA的改变，如基因组不稳定性、高肿瘤突变负荷和/或DNA损伤修复缺陷，与免疫治疗和化疗的反应有关。放射和/或化疗产生的细胞毒性或代谢应激可作为有效的免疫触发剂和引发免疫应答。损伤或应激介导的核酸传感途径的激活触发I型干扰素（IFN-I）应答，其激活先天免疫细胞和自然杀伤细胞，促进树突状细胞的成熟，并刺激适应性免疫。虽然PDAC表现出具有吸引免疫细胞潜力的内在特征，特别是在化疗后，但这些免疫感应机制是无效的。了解先天免疫触发因素中的缺陷使PDAC肿瘤免疫界面不那么有效，或者T细胞功能如何受到抑制，将有助于开发更有效的治疗方法，并利用免疫系统获得持久的结果。本文就IFN-Ⅰ在PDAC中促进肿瘤细胞-免疫细胞间串扰的作用作一综述。我们将讨论PDAC肿瘤细胞如何绕过IFN-I信号通路，并探索如何选择或重新参与这些通路以提高治疗效果。
Immunotherapy has revolutionized the treatment of many cancer types. However, pancreatic ductal adenocarcinomas (PDACs) exhibit poor responses to immune checkpoint inhibitors with immunotherapy-based trials not generating convincing clinical activity. PDAC tumors often have low infiltration of tumor CD8+ T cells and a highly immunosuppressive microenvironment. These features classify PDAC as immunologically “cold.” However, the presence of tumor T cells is a favorable prognostic feature in PDAC. Intrinsic tumor cell properties govern interactions with the immune system. Alterations in tumor DNA such as genomic instability, high tumor mutation burden, and/or defects in DNA damage repair are associated with responses to both immunotherapy and chemotherapy. Cytotoxic or metabolic stress produced by radiation and/or chemotherapy can act as potent immune triggers and prime immune responses. Damage- or stress-mediated activation of nucleic acid-sensing pathways triggers type I interferon (IFN-I) responses that activate innate immune cells and natural killer cells, promote maturation of dendritic cells, and stimulate adaptive immunity. While PDAC exhibits intrinsic features that have the potential to engage immune cells, particularly following chemotherapy, these immune-sensing mechanisms are ineffective. Understanding where defects in innate immune triggers render the PDAC tumor–immune interface less effective, or how T-cell function is suppressed will help develop more effective treatments and harness the immune system for durable outcomes. This review will focus on the pivotal role played by IFN-I in promoting tumor cell–immune cell cross talk in PDAC. We will discuss how PDAC tumor cells bypass IFN-I signaling pathways and explore how these pathways can be co-opted or re-engaged to enhance the therapeutic outcome.
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