Immunological Modification of the Head and Neck Cancer Microenvironment by Short Chain Fatty Acids

Abstract

Recently, immune checkpoint inhibitors (ICIs) have emerged as a new option for the treatment of head and neck cancer. However, improving their efficacy remains a challenge, and approaches to the tumor microenvironment are important. While intestinal bacteria and their metabolites, short-chain fatty acids (SCFAs), have attracted much attention, the effects of SCFAs on cancer and immune cells are still unclear. In this study, we decided to focus on SCFA-A, one of the SCFAs that have the strongest effect on immune activity in preliminary experiments, to clarify its effects on cancer and immune cells. By co-culturing cancer cells and T cells at different cell concentrations, we reproduced the three sequential phases of cancer immunoediting: cancer and T cells in equilibrium, cancer-dominant, and T cell-dominant. SCFA-A was directly added to the co-cultures of cancer cells and T cells. In addition, SCFA-A was orally administered to a tumor-bearing mouse model to clarify the mechanism of the anti-tumor effect of SCFA-A in the tumor microenvironment. SCFA-A inhibited tumor growth in the co-culture of cancer cells and T cells, and oral administration of SCFA-A to a tumor-bearing mouse model increased anti-PD-1 activity. This study is expected to improve the efficacy of the treatment of ICIs and may lead to drug discovery for cancer immunotherapy and the discovery of new biomarkers.