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

Abstract

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.

Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy

“…Lirilumab, in combination with ipilimumab, is being tested for treatment of advanced solid tumors in a clinical trial (NCT01750580), but the trial is still recruiting patients [ 212 ]. In vitro evidence suggests that lirilumab enhances killing of head and neck squamous cell carcinoma (HNSCC) cells by NK cells [ 213 ]. Enhancement of anti-tumoral effects of lirilumab, in combination with rituximab, has been well demonstrated in hematologic malignancies both in vivo and in vitro [ 214 ].…”

The prognostic role of NK cells and their ligands in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis

“…12,13 The antitumor effect of cetuximab is strengthened by binding the FcY receptor on NK cells enabling antibody-dependent cellular cytotoxicity (ADCC). 14 Immunological markers have shown to be prognostic indicators, even superior to the TNM staging system. 15 In lung, colorectal and breast cancer, studies have shown that tumorinfiltrating lymphocytes have a favorable prognostic role.…”

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

“…HNSCCs are among the most immune-infiltrated cancers, and several mechanisms are implemented by tumor cells to escape to the host immune defense system (190,191). The immunemodulatory effect of CTX treatment, in particular ADCC, might be inhibited by cancer cells through several mechanisms inducing T cell exhaustion/impairment and all CTX resistance (67,97,(192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203)(204). Indeed, to counteract the antitumor activity of CTX, tumor cells express TGF-b, which inhibits the expression of cytotoxic effector molecules in immune cells (Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-g) and suppresses their ability to induce cetuximab-mediated ADCC (97).…”