Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy

Abstract

The combination immunotherapies, including those with atezolizumab and bevacizumab (Atez/Bev), have become standard therapy for hepatocellular carcinoma (HCC). However, its efficacy remains limited and reliable biomarkers are lacking. In this study, we analyzed paired tumor and background liver tissues from Atez/Bev-treated HCC patients and found that high programmed cell death-1 (PD-1) expression in CD8+ tumor-infiltrating lymphocytes (TILs) correlated with therapeutic response independent of etiology. RNA sequencing on the tumor samples revealed that the branched-chain amino acid (BCAA)-related metabolic pathway was enriched in the group with high PD-1 expression in CD8⁺ TILs. Along with in vitro experiments, we identified the importance of BCAAs for activation and differentiation of CD8+ T cells. In addition, BCAA metabolism was related to response to PD-1 blockade in not subcutaneous but intrahepatic mouse model–specific manner. Actually, public dataset analyses revealed that high expression of BCAT1, a key enzyme in BCAA metabolism, was associated with poor prognosis in HCC, but not in other cancer types. These findings suggest the importance of liver-specific BCAA metabolism in antitumor immunity and highlight the need to assess the tumor microenvironment within its organ-specific metabolic context. While cancer immunotherapy has advanced liver cancer treatment, many patients still do not experience long-term benefits. In this study, we analyzed samples from liver cancer patients and found that branched-chain amino acids (BCAAs), key nutrients found in the liver, are essential for cancer-fighting immune cells to do their job. We demonstrated that these immune cells and cancer cells actively compete for BCAAs within the liver. This competition can weaken the immune cells, making the treatment less effective. Our findings highlight that to improve cancer therapies, we need to understand how the unique metabolic environment of a specific organ affects the body’s immune response.