Abstract
Objective In conjunction with advances made in cytotoxic chemotherapy, radiation, and surgery, immunotherapy has emerged as a fourth modality of treatment for head and neck squamous cell carcinoma (HNSCC). Understanding the mechanisms by which HNSCC evades immune-mediated control will aid in the development of new therapies to augment an antitumor immune response. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell surface receptor that is expressed on malignant cells and lymphocytes such as natural killer (NK) cells. We sought to determine whether tumor-derived CEACAM1 inhibits NK cell cytotoxicity and whether blockade of CEACAM1 restores antitumor immunity. Study Design In vitro HNSCC cell line study. Setting Research laboratory. Subject and Methods We utilized a real-time cell analyzer to assess NK cell cytotoxicity against an oral squamous cell carcinoma cell line after modulating CEACAM1 expression by cytokines and shRNA knockdown of CEACAM1 expression. Results NK cells and HNSCC cells both demonstrated cytokine-inducible expression of CEACAM1. Coincubation of NK cells and HNSCC cells resulted in the upregulation of CEACAM1 on the tumor cells. When compared with CEACAM1- cells, CEACAM1+ tumor cells exhibited increased cell growth and increased size and number of organoids in 3-dimensional culture. Notably, CEACAM1+ HNSCC cells were more resistant to NK cell-mediated killing, but the inhibited expression of CEACAM1 by an shRNA construct restored NK cell cytotoxicity. Conclusion Together, these data indicate that CEACAM1 acts as an inducible checkpoint molecule, and they support the idea that targeting CEACAM1 could serve as a novel immunotherapy approach in HNSCC.