Genetic alteration of class I HLA in cutaneous T-cell lymphoma

• Published in: Blood 2024-10
• Main Authors: Kwang, Alexa C., Duran, George E., Fernandez-Pol, Sebastian, Najidh, Safa, Li, Shufeng, Bastidas Torres, Armando N., Wang, Erica B., Herrera, Melba, Bandali, Tarek I., Kurtz, David M., Kim, Youn H., Khodadoust, Michael S.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2024024817

•Genetic alteration of class I HLA genes is common in advanced cutaneous T-cell lymphoma but rarely affects total class I HLA expression.•Genetic events involving HLA in CTCL are often dynamic and subclonal. [Display omitted] Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCLs). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides or Sézary syndrome. Targeted DNA sequencing, including coverage of HLA loci, revealed at least 1 HLA abnormality in 26 of 65 patients (40%). Twelve unique somatic HLA mutations were identified across 9 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 a decrease in the total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presenting 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 that HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed that disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient who received pembrolizumab and in whom resistance to pembrolizumab was associated with the 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.