Abstract 1690: NKG2A immune checkpoint blockade potentiates cetuximab induced ADCC in head and neck cancer preclinical model
Authors: Soulas Caroline , Lalanne Ana , Bonnafous Cécile , Hoffman Caroline , Bonnet Elodie , Dujardin Arnaud , Breso Violette , Bléry Mathieu , Lantz Olivier , Remark Romain , Vivier Eric , Andre Pascale 
Published: August 2018

Monalizumab (IPH2201) is a first-in-class humanized IgG4 targeting NKG2A (Natural Killer Group 2A), which is expressed as a heterodimer with CD94 at the surface of subsets of NK (Natural Killer) cells, γδ T cells and tumor infiltrating CD8+ T cells. This inhibitory receptor binds to HLA-E (Human Leukocytes Antigen-E) molecules that are frequently up-regulated on human cancer cells, preventing from killing by NKG2A+ immune cells. HLA-E is expressed on most of the patients with Head and Neck Squamous Cell Cancer (HNSCC). Monalizumab blocks the binding of CD94/NKG2A to HLA-E, reducing inhibitory signaling thereby unleashing NK and T cell responses. High expression of EGFR occurs in most epithelial malignancies and particularly in HNSCC and is associated with poor prognosis. The anti-EGFR monoclonal antibody cetuximab (Ctx) is thought to act through blocking oncogenic signaling and by inducing Fcγ receptor-mediated antibody dependent cell cytotoxicity (ADCC) which involves human NK cells. We investigated ex vivo and in vitro the rationale of combining monalizumab with Ctx in the treatment of oral cancers. We first analyzed formalin-fixed paraffin-embedded samples of HNSCC patients by immunohistochemistry (n=65). We confirmed that HLA-E was expressed on carcinoma cells in all patients. We also observed that most of the tumors were highly infiltrated by CD8+ T cells both in the tumor beds and in the stroma and that the majority of tumors were also infiltrated by NKp46+ NK cells in higher numbers in the non-metastatic tumors. Interestingly, HNSCC was found as being one of the tumor types with the highest NKp46+ cell density as compared with renal cell carcinoma, non-small cell lung cancer, colorectal cancer or pancreatic tumors. Moreover CD94+ lymphocytes were detected in the stroma and tumor beds in close contact to tumor cells in about half of the patients. Using multicolor flow cytometry, NK cells and CD8+ T cells from tumor and non-involved adjacent tissues, metastatic lymph nodes and peripheral blood from patients relapsing post-chemotherapy were characterized for expression of activating and inhibitory receptors. Interestingly, NKG2A expression was higher on tumor infiltrating NK cells (CD56dim or CD56bright) and CD8+ T cell compared to the one observed in non-involved adjacent tissue, metastatic lymph node or blood. In vitro, monalizumab increased CD107 mobilization and CD137 upregulation on NKG2A+ NK cells in response to HNSCC cell lines with endogenous HLA-E expression and enhanced Ctx-mediated ADCC in a dose dependent manner. Altogether, these data support the rationale for investigating monalizumab in HNSCC patients and in combination with cetuximab in clinical trials (NCT02643550).

Citation Format: Caroline Soulas, Ana Lalanne, Cécile Bonnafous, Caroline Hoffman, Elodie Bonnet, Arnaud Dujardin, Violette Breso, Mathieu Bléry, Olivier Lantz, Romain Remark, Eric Vivier, Pascale Andre. NKG2A immune checkpoint blockade potentiates cetuximab induced ADCC in head and neck cancer preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1690.