Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma

Faden DL, Concha-Benavente F, Chakka AB, McMichael EL, Chandran U, Ferris RL. Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma. Head Neck. 2019 Mar 4. doi: 10.1002/hed.25726. [Epub ahead of print]. PMID: 30828910.

BACKGROUND:

Mechanisms of resistance to immune-modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor-specific monoclonal antibody (mAb) therapy.

METHODS:

HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen-C (HLA-C) and the effect of KIR blockade were assessed in HNSCC cell lines.

RESULTS:

Nonresponders to cetuximab had an increased rate of mutations in HLA-C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab-activated natural killer (NK) cells induced upregulation of HLA-C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti-KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001).

CONCLUSIONS:

Alterations in HLA-C may provide a mechanism of immune evasion through disruption of NK activation.

Publication Year: 
2019
Faculty Author: 
Publication Credits: 
Faden DL, Concha-Benavente F, Chakka AB, McMichael EL, Chandran U, Ferris RL
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