Abstract 33: CEACAM1 blockade increases NK cell cytotoxicity in head and neck squamous cell carcinoma

Abstract

Abstract In conjunction with advances made in cytotoxic chemotherapy, radiation, and surgery, immunotherapy has emerged in recent years as a promising fourth modality of treatment for head and neck squamous cell carcinoma (HNSCC). Cetuximab, an anti-EGFR antibody, is now routinely used as an adjunct to radiation therapy and in the recurrent/metastatic setting following treatment failure with concurrent cisplatin and radiation. Understanding the fundamental mechanisms by which HNSCC evades the immune system will aid the development of new therapies and strategies to augment an antitumor immune response. Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is a cell surface receptor that is expressed on HNSCC cells, as well as on lymphocytes, such as NK cells. Overexpression of CEACAM1 in HNSCC has been associated with a poor prognosis, higher clinical stage, recurrence, and lymph node metastasis. A phase I trial (NCT02346955) of an anti-CEACAM1 antibody is currently underway for a variety of non-HNSCC malignancies. We demonstrate that in mice inoculated with TUBO-EGFR, a murine cancer cell line, treatment with an anti-CEACAM1 antibody rescues NK cell effector function from exhaustion resulting in reduced tumor growth and enhanced antibody-dependent cell-mediated cytotoxicity. The addition of Cetuximab has an additive effect and results in additional tumor shrinkage. Thus, these data indicate that CEACAM1 is a novel checkpoint molecule on NK cells. CEACAM1 is also expressed on tumor cells themselves; its expression in HNSCC is associated with suppression of NK cell cytotoxicity. In vitro co-incubation of NK cells with PCI-13, a human HNSCC cell line, results in IFNγ-mediated upregulation of CEACAM1 on the tumor cells. IFNγ-exposed cells are more resistant to NK cytotoxicity compared to untreated cells, suggesting that immune pressure induces upregulation of NK inhibitors. Importantly, CEACAM1+ NK cells have decreased cytotoxicity against HNSCC tumor cells compared to CEACAM1- NK cells, but the addition of an anti-CEACAM1 antibody restores NK cell effector function. Together, these data indicate that CEACAM1 acts as a checkpoint molecule and that a blocking antibody against CEACAM1 releases its immunosuppressive effects and could serve as a novel immunotherapy for HNSCC. Citation Format: Kenric Tam, Yunqin Lee, David Schoppy, John B. Sunwoo. CEACAM1 blockade increases NK cell cytotoxicity in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 33.