Somatic 9p24.1 alterations in HPV – head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity

• DOI: 10.1073/pnas.2213835119
• Publication Date: 2022-11-17T18:37:28Z
• Authors: Xin Zhao; Ezra E. W. Cohen; William N. William; Joy J. Bianchi; Jim P. Abraham; Daniel Magee; David B. Spetzler; J. Silvio Gutkind; Ludmil B. Alexandrov; Webster K. Cavenee; Scott M. Lippman; Teresa Davoli
• Keywords: Immune checkpoint; CTCF

Somatic copy number alterations (SCNAs), generally ( 1 ) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors 2 ); however, genomic regions mediating these effects are unclear probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus–negative (HPV – head neck squamous cancer (HNSC), associated with immune-cold tumor microenvironment (TME) signal, recent evidence suggested that this TME-cold phenotype greatly enhanced 9p21 deletion size, notably encompassing band 9p24.1 3 ). Here, we report multi-omic, -threshold continuous-variable dissection 9p24 loci (including depth degree somatic alteration each at locus, gene band) TME four HPV HNSC cohorts. Preferential deletion, CD8 T-cell associations were observed, driven by loss, in turn essential telomeric regulatory element, JAK2-CD274 . Surprisingly, same region gains hot. Related 9p21-TME analyses less evident. Inherent 9p-band-level influences anti-PD1 ICT survival rates, coincident patterns, also observed. At a whole-transcriptome expression threshold 60th percentile, rate exceeded lower percentiles chemotherapy; below transcript threshold, inferior chemotherapy, the latter unaffected level P- values < 0.01, including PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome 10 solid-tumor types suggest 9p-related findings could relevant cancers, which gain/immune-hot exist.