The impact of liver metastases on immune checkpoint inhibitor effectiveness in patients with solid tumor malignancies has been the focus of several recent clinical and translational studies.We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and NSCLC patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with PD-1 and PDL-1 inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a 2 site MC38 model appear to delete CD8+ T cells in a FasL dependent manner. In addition, Treg activation was observed and contributed to the distal immunosuppression. Finally, we discuss the some of the interventions reported to address liver immune suppression such as radiation therapy, combination checkpoint blockade and Treg depletion.Research.

CD8+ T cells are critical for the immune response to pathogens and tumors, and CD8+ T cell memory protects against repeat infections. In this study, we identify the activating transcription factor 7 interacting protein (ATF7ip) as a critical regulator of CD8+ T cell immune responses. Mice with a T cell–specific deletion of ATF7ip have a CD8+ T cell–intrinsic enhancement of Il7r expression and Il2 expression leading to enhanced effector and memory responses. Chromatin immunoprecipitation sequencing studies identified ATF7ip as a repressor of Il7r and Il2 gene expression through the deposition of the repressive histone mark H3K9me3 at the Il7r gene and Il2–Il21 intergenic region. Interestingly, ATF7ip targeted transposable elements for H3K9me3 deposition at both the IL7r locus and the Il2–Il21 intergenic region, indicating that ATF7ip silencing of transposable elements is important for regulating CD8+ T cell function. These results demonstrate a new epigenetic pathway by which IL-7R and IL-2 production are constrained in CD8+ T cells, and this may open up new avenues for modulating their production.