肿瘤相关抗原负担与免疫检查点阻断剂在T细胞耗竭水平较低的肿瘤中的获益相关。

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Yue Wang, Mengying Hu, Olivera J Finn, Xiao-Song Wang
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引用次数: 0

摘要

肿瘤相关抗原(TAA)是癌症疫苗的重要靶点。然而,基于 TAA 的疫苗尚未在临床试验中充分发挥潜力。与此相反,免疫检查点阻断(ICB)已成为一种有效的疗法,可使特定癌症患者产生持久的反应。迄今为止,关于 TAAs 与 ICB 治疗效果之间可推广的关联报道很少,大多数研究都集中在黑色素瘤上,因为黑色素瘤是突变率最高的癌症。在本研究中,我们根据已知和推测的 TAA 开发了 TAA 负担(TAB)算法,并研究了 TAB 与 ICB 受益的关联。对接受抗PD-L1治疗的IMVigor210尿路上皮癌患者队列的分析表明,高肿瘤突变负荷(TMB)削弱了TAB与ICB获益的相关性。此外,在免疫细胞PD-L1染色为阴性的肿瘤中,TAB与ICB疗效相关,而免疫细胞PD-L1染色水平高则与T细胞衰竭有关。独立临床数据集(包括使用抗PD1/PD-L1药物治疗的尿路上皮癌队列和头颈癌新辅助抗PD1试验)的验证证实了TAB与T细胞衰竭程度低的肿瘤的ICB获益相关。泛癌症分析表明,在大多数癌症实体中,T细胞衰竭程度较高的肿瘤显示出较低的TAB水平,这意味着在已建立抗肿瘤免疫的肿瘤中可能存在对TAAs的免疫编辑。我们的研究对TAAs与ICB反应之间缺乏关联的普遍观点提出了质疑。它还强调了未来研究TAAs免疫原性的必要性,以及在T细胞衰竭水平较低的肿瘤中基于TAAs的疫苗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumor-Associated Antigen Burden Correlates with Immune Checkpoint Blockade Benefit in Tumors with Low Levels of T-cell Exhaustion.

Tumor-associated antigens (TAA) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMvigor210 patient cohort of urothelial carcinoma treated with anti-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. It also underscores the need for future investigations into the immunogenicity of TAAs and TAA-based vaccine strategies in tumors with low levels of T-cell exhaustion.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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