涉及 I 类 HLA 的异常在许多淋巴瘤亚型中很常见，但尚未在皮肤 T 细胞淋巴瘤 (CTCL) 中进行广泛研究。我们对 65 名晚期蕈样肉芽肿 (MF) 或塞扎里综合征 (SS) 患者的 I 类 HLA 异常的发生情况进行了描述。包括 HLA 基因座覆盖范围的靶向 DNA 测序显示 26/65 名患者 (40%) 至少有一种 HLA 异常。在 9 名患者中发现了 12 种独特的体细胞 HLA 突变，并且发现 HLA 杂合性丢失或双等位基因丢失影响了 24 名患者。尽管特定的 HLA 等位基因通常被破坏，但这些事件与 I 类 HLA 总表达减少无关。遗传事件优先破坏能够呈现更多推定新抗原的 HLA 等位基因。 HLA 异常与其他遗传免疫逃避事件同时发生，并且与较差的无进展生存期相关。单细胞分析表明 HLA 异常通常是亚克隆的。通过对连续样本的分析，我们观察到破坏 I 类 HLA 事件在疾病过程中动态变化。 HLA 破坏的动态在接受帕博利珠单抗治疗的患者中尤为突出，其中对帕博利珠单抗的耐药性与 HLA 突变的消除相关。总体而言，我们的研究结果表明，基因组 I 类 HLA 异常在晚期 CTCL 中很常见，可能是了解 CTCL 免疫治疗效果的重要考虑因素。版权所有 © 2024 美国血液学会。

Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCL). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). Targeted DNA sequencing including coverage of HLA loci revealed at least one HLA abnormality in 26/65 patients (40%). Twelve unique somatic HLA mutations were identified across nine patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with decreased total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presentation of greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient receiving pembrolizumab, where resistance to pembrolizumab was associated with elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.Copyright © 2024 American Society of Hematology.