Hürthle细胞癌（HCC）是一种罕见的甲状腺癌，具有高发远处转移和复发率。加上缺乏对HCC有效的系统治疗方法，这些因素导致临床预后不良。HCC的免疫学特征尚未明确定义，对免疫检查点阻断的应答率也未报告。需要更全面地了解免疫景观以及预测检查点抑制剂应答的因素。我们对40个肿瘤进行了RNA测序，以表征HCC的新抗原景观和免疫微环境。我们分析了转录谱、肿瘤浸润免疫细胞群体和T细胞激活/功能障碍的指标，并将其与肿瘤变异负担、新抗原负担、线粒体突变和染色体单亲合子失异损失（LOH）等遗传特征进行相关分析。最后，将复发患者的免疫景观与无复发患者进行比较。HCC肿瘤显示出较低水平的免疫浸润，更具侵袭性的广泛浸润表型与免疫耗竭相关。肿瘤变异负担、新抗原负担、程序性细胞死亡配体1（PD-L1）表达和免疫浸润评分之间存在负相关关系。在染色体单亲合子失异损失或单倍化的全染色体丧失HCC肿瘤中，免疫浸润水平最低。复发的HCC肿瘤显示出与染色体全丧失和有氧糖酵解相关的免疫缺乏微环境。这些发现为HCC的功能免疫景观和免疫微环境提供了新见解。我们的数据确定了这些研究不足且常常致命的癌症的潜在免疫学弱点。HCC的免疫景观还没有明确定义，免疫疗法的应答率也没有报告。作者发现HCC的免疫微环境受到耗竭影响。这种免疫抑制与全染色体失异损失和单亲合子失相有关，导致整个基因组上的染色体丢失。© 2023 作者；发表于美国癌症研究协会。

Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers.The immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome.© 2023 The Authors; Published by the American Association for Cancer Research.