The Microbiome in Immuno-oncology.

The field of cancer therapy has been revolutionized through the use of immunotherapy, and treatment with these therapies now spans from early to late stage, and even into prevention. However, there are still a significant proportion of patients who do not derive long-term benefit from monotherapy and even combined therapy regimens, and novel approaches are needed to enhance therapeutic responses. Additionally, ideal biomarkers of response to immunotherapy are lacking and are critically needed. An emerging area of interest in immuno-oncology (IO) is the microbiome, which refers to the collection of microbes (and their genomes) that inhabit an individual and live in symbiosis. There is now evidence that these microbes (particularly those within the gut) impact host physiology and can impact responses to immunotherapy. The field of microbiome research in immuno-oncology is quickly emerging, with the potential use of the microbiome (in the gut as well as in the tumor) as a biomarker for response to IO as well as a therapeutic target. Notably, the microbiome may even have a role in toxicity to therapy. The state of the science in microbiome and IO are discussed and caveats and future directions are outlined to provide insights as we move forward as a field.

Clinical Importance of the lncRNA NEAT1 in Cancer Patients Treated with Immune Checkpoint Inhibitors.

PURPOSE: mAbs targeting the PD-1/PD-L1 immune checkpoint are powerful tools to improve the survival of patients with cancer. Understanding the molecular basis of clinical response to these treatments is critical to identify patients who can benefit from this immunotherapy. In this study, we investigated long noncoding RNA (lncRNA) expression in patients with cancer treated with anti-PD-1/PD-L1 immunotherapy. EXPERIMENTAL DESIGN: lncRNA expression profile was analyzed in one cohort of patients with melanoma and two independent cohorts of patients with glioblastoma (GBM) undergoing anti-PD-1/PD-L1 immunotherapy. Single-cell RNA-sequencing analyses were performed to evaluate lncRNA expression in tumor cells and tumor-infiltrating immune cells. RESULTS: We identified the lncRNA NEAT1 as commonly upregulated between patients with melanoma with complete therapeutic response and patients with GBM with longer survival following anti-PD-1/PD-L1 treatment. Gene set enrichment analyses revealed that NEAT1 expression was strongly associated with the IFNγ pathways, along with downregulation of cell-cycle-related genes. Single-cell RNA-sequencing analyses revealed NEAT1 expression across multiple cell types within the GBM microenvironment, including tumor cells, macrophages, and T cells. High NEAT1 expression levels in tumor cells correlated with increased infiltrating macrophages and microglia. In these tumor-infiltrating myeloid cells, we found that NEAT1 expression was linked to enrichment in TNFα/NFκB signaling pathway genes. Silencing NEAT1 suppressed M1 macrophage polarization and reduced the expression of TNFα and other inflammatory cytokines. CONCLUSIONS: These findings suggest an association between NEAT1 expression and patient response to anti-PD-1/PD-L1 therapy in melanoma and GBM and have important implications for the role of lncRNAs in the tumor microenvironment.

Normal Iron Homeostasis Requires the Transporter SLC48A1 for Efficient Heme-Iron Recycling in Mammals.

In mammals over 65% of the total body iron is located within erythrocytes in the heme moieties of hemoglobin. Iron homeostasis requires iron absorbed from the diet by the gut as well as recycling of iron after the destruction of senescent erythrocytes. Senescent erythrocytes are engulfed by reticuloendothelial system macrophages where hemoglobin is broken down in the lysosomes, releasing heme for iron recovery in the cytoplasm. We recently showed that the SLC48A1 protein is responsible for transporting heme from the lysosome to the cytoplasm. CRISPR generated SLC48A1-deficient mice accumulate heme in their reticuloendothelial system macrophages as hemozoin crystals. Here we describe additional features of SLC48A1-deficient mice. We show that visible hemozoin first appears in the reticuloendothelial system macrophages of SLC48A1-deficient mice at 8 days of age, indicating the onset of erythrocyte recycling. Evaluation of normal and SLC48A1-deficient mice on iron-controlled diets show that SLC48A1-mediated iron recycling is equivalent to at least 10 parts per million of dietary iron. We propose that mutations in human SLC48A1 could contribute to idiopathic iron disorders.