Immunogenomic Correlates of Response to Cetuximab in Head and Neck Squamous Cell Carcinoma

Abstract

Immune evasion is a sine qua non for cancer development. Mechanisms of resistance to immune modulating therapeutics in cancer are poorly understood. Less than 20% of patients with HNSCC have a lasting response to cetuximab. We hypothesized that acquired somatic alterations may provide a mechanism of immune evasion in cetuximab failure. Here, using a novel cohort of HNSCC patients treated with neoadjuvant cetuximab, we investigated mechanisms of immune escape from cetuximab therapy. 20 HNSCC tumors (9 non-responders, 11 responders) from a recently completed prospective trial of neoadjuvant cetuximab monotherapy with well annotated response data underwent whole exome sequencing. KIR expression on NK cells, HLA-C expression on HNSCC cells, IFNγ release from NK cells and tumor killing by the anti-KIR monoclonal antibody, lirilumab, were assessed in vitro. Potentially deleterious somatic alterations (missense mutations and LOH) in HLA-C in non-responders to cetuximab were statistically increased compared to responders and HNSCCs in the TCGA (Table 1). Canonical pathway analysis similarly identified NK cell signaling pathway genes as statistically overly-mutated. HLA-C is the ligand for KIR on NK cells, modulating activation versus latency. To explore this potential mechanism of resistance we examined the relationship between KIR expression and IFNγ release from NK cells, HLA-C expression on HNSCC cells and tumor killing in the presence of lirilumab. We found that NK cells from HNSCC patients maintain expression of KIRs and that cetuximab-activated NK cells induce upregulation of HLA-C on tumor cells, due to cetuximab induced IFNγ release. Blocking NK inhibitory KIR signaling with lirilumab increased cell killing of HNSCC cells. Somatic alterations in HLA-C may provide a mechanism of immune evasion from cetuximab therapy through disruption of NK cell activation, as supported by the identification of somatic HLA-C alterations in patients who fail cetuximab therapy. In vitro assessment of KIR and HLA-C expression on HNSCC cells, as well as cell killing in the presence of KIR modulation, further support this hypothesis. These findings open the door for additional investigations into the role of HLA alterations in HNSCC and the potential use of HLA-C alterations as a biomarker for cetuximab therapy in HNSCC.Abstract LBA7; Table 1CohortHLA-C Mutation RateP valueNon-Responders67%<.00001Responders9%TCGA2% Open table in a new tab