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

• 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.

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.