The role of stromal cells in resistance to cetuximab treatment in head and neck cancer

Abstract:

Introduction: Resistant to cetuximab, an antibody that blocks the epithelial growth factor receptor (EGFR), is a major problem in the treatment of head and neck cancer (HNC) patients. Cetuximab is effective in a fraction of HNC patients, whom eventually all develop resistance that lead to disease relapse. The resistance to cetuximab is known to be mediated, in part, by cells surrounding the tumor cells, such a fibroblast. However, the mechanisms underlying the migration, accumulation, and differentiation of stromal cells are still unclear.

Material and method: We used patient-derived xenograft (PDX) models to investigate the interaction between tumor cells and their stroma. Five different PDXs were implanted in NOD.SCID mice and the response to cetuximab was measured. Molecular and pathological analyses of tumors using RNA sequencing and immunohistochemistry (IHC), respectably, were performed to gain insight on the changes that occur in the tumor and their stroma during cetuximab treatment. Specifically, staining of fibroblasts (aSMA), endothelial cells (CD31), tumor cells (KRT14), epithelial to mesenchymal markers (E-cadherin and Vimentin), and proliferation (KI67) were tested in PDXs treated with vehicle or cetuximab.

Results and discussion: All five PDXs were sensitive to cetuximab, as all treated mice displayed a significant tumor growth inhibition. IHC staining showed a decrease in the amount of proliferating tumor cells, indicated by co-staining of KRT14 and Ki67. We further observed a downregulation in E-cadherin on tumor cells, while Vimentin was upregulated in the stroma and the tumor cells after cetuximab treatment. In addition, in 3 of the 5 PDXs the amount of tumor associated fibroblast cells (aSMA staining) was decreased.

Conclusion: Cetuximab treatment affects the plasticity and heterogeneity of tumor cells and their microenvironment.