Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China; Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China.
Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China; School of Medicine, Shanghai University, Shanghai 200444, China.
J Hepatol. 2023 Dec;79(6):1435-1449. doi: 10.1016/j.jhep.2023.08.024. Epub 2023 Sep 7.
BACKGROUND & AIMS: Remodeling the tumor microenvironment is a critical strategy for treating advanced hepatocellular carcinoma (HCC). Yet, how distinct cell populations in the microenvironment mediate tumor resistance to immunotherapies, such as anti-PD-1, remains poorly understood.
We analyzed the transcriptomic profile, at a single-cell resolution, of tumor tissues from patients with HCC scheduled to receive anti-PD-1-based immunotherapy. Our comparative analysis and experimental validation using flow cytometry and histopathological analysis uncovered a discrete subpopulation of cells associated with resistance to anti-PD-1 treatment in patients and a rat model. A TurboID-based proximity labeling approach was deployed to gain mechanistic insights into the reprogramming of the HCC microenvironment.
We identified CD10ALPL neutrophils as being associated with resistance to anti-PD-1 treatment. These neutrophils exhibited a strong immunosuppressive activity by inducing an apparent "irreversible" exhaustion of T cells in terms of cell number, frequency, and gene profile. Mechanistically, CD10ALPL neutrophils were induced by tumor cells, i.e., tumor-secreted NAMPT reprogrammed CD10ALPL neutrophils through NTRK1, maintaining them in an immature state and inhibiting their maturation and activation.
Collectively, our results reveal a fundamental mechanism by which CD10ALPL neutrophils contribute to tumor immune escape from durable anti-PD-1 treatment. These data also provide further insights into novel immunotherapy targets and possible synergistic treatment regimens.
Herein, we discovered that tumor cells reprogrammed CD10ALPL neutrophils to induce the "irreversible" exhaustion of T cells and hence allow tumors to escape from the intended effects of anti-PD-1 treatment. Our data provided a new theoretical basis for the elucidation of special cell populations and revealed a molecular mechanism underpinning resistance to immunotherapy. Targeting these cells alongside existing immunotherapy could be looked at as a potentially more effective therapeutic approach.
重塑肿瘤微环境是治疗晚期肝细胞癌（HCC）的关键策略。然而，微环境中不同细胞群体如何介导肿瘤对免疫疗法（如抗 PD-1）的耐药性仍知之甚少。
我们以单细胞分辨率分析了计划接受抗 PD-1 为基础的免疫治疗的 HCC 患者肿瘤组织的转录组谱。我们通过流式细胞术和组织病理学分析进行了比较分析和实验验证，发现了一个与患者和大鼠模型中抗 PD-1 治疗耐药相关的离散细胞亚群。我们使用 TurboID 基于邻近标记的方法来深入了解 HCC 微环境的重编程机制。
我们确定 CD10ALPL 中性粒细胞与抗 PD-1 治疗耐药有关。这些中性粒细胞通过诱导 T 细胞在数量、频率和基因谱上表现出明显的“不可逆转”耗竭，表现出强烈的免疫抑制活性。从机制上讲，肿瘤细胞诱导了 CD10ALPL 中性粒细胞，即肿瘤分泌的 NAMPT 通过 NTRK1 重编程 CD10ALPL 中性粒细胞，使其保持在不成熟状态，并抑制其成熟和激活。
总之，我们的研究结果揭示了 CD10ALPL 中性粒细胞促进肿瘤从持久的抗 PD-1 治疗中免疫逃逸的基本机制。这些数据还为新型免疫治疗靶点和可能的协同治疗方案提供了进一步的见解。
在这里，我们发现肿瘤细胞重编程 CD10ALPL 中性粒细胞诱导 T 细胞的“不可逆转”耗竭，从而使肿瘤逃避抗 PD-1 治疗的预期效果。我们的数据为阐明特殊细胞群体提供了新的理论基础，并揭示了免疫治疗耐药的分子机制。靶向这些细胞以及现有的免疫疗法可能被视为一种更有效的治疗方法。
