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When this relay circuitry is disrupted from injury or disease, it is devastating to patients due to the lack of native recovery in central nervous system (CNS) tissues. Spinal interneurons (INs) relay sensory and motor control information between the brain and body. In addition, given a role for APOBEC3B in cancer mutagenesis, it may also be possible for information from the interaction to be used to develop DNA deaminase inhibitors. A molecular understanding of this pathogen-host interaction has potential to inform the development of drugs that block the interaction and liberate the natural antiviral activity of APOBEC3B. Evolutionary optimization is suggested by unique insertions in BORF2 absent from other ribonucleotide reductases and preferential binding to APOBEC3B relative to the highly related APOBEC3A and APOBEC3G enzymes. Cryo-EM studies of APOBEC3B-BORF2 complexes reveal a large >1000-Г…2 binding surface composed of multiple structural elements from each protein, which effectively blocks the APOBEC3B active site from accessing single-stranded DNA substrates. A recent example is neutralization of the nuclear DNA cytosine deaminase APOBEC3B by the Epstein-Barr virus (EBV) ribonucleotide reductase subunit BORF2.

Viruses use a plethora of mechanisms to evade immune responses. This analysis identifies candidate biomarkers and therapeutic targets such as TIM-3, CCR4, and CXCR3 that are relevant for combination treatment strategies in immuno-oncology and cellular therapies. We demonstrate that, far from being histo-pathologically monotonous, DLBCL has a complex tumor architecture, and that changes in tumor topology can be correlated with clinically relevant features. This is the first study to integrate tumor mutational profiling, cell of origin classification, and multiplexed immuno-phenotyping of the TME into a spatial analysis of DLBCL at the single cell level. Finally, the spatial analysis allowed us to identify markers such as CXCR3, which are associated with penetration of immune cells into immune desert regions, with important implications for engineered cellular therapies. We created a spatial classification of tumor cells and identified tumor-centric sub-regions of immune activation, immune suppression, and immune exclusion within the topology of DLBCL. To understand the poor response of DLBCL to immune checkpoint inhibitors (ICI), we compared our results to IMC data from Hodgkin lymphoma (HL), a cancer highly responsive to ICI, and observed differences in the expression of PD-L1, PD-1, and TIM-3.

Here we used imaging mass cytometry (IMC) on 33 cases of diffuse large B cell lymphoma (DLBCL) to characterize tumor and immune cell architecture and correlate it to clinicopathological features such as cell of origin, gene mutations, and responsiveness to chemotherapy. Multiplexed immune cell profiling of the tumor microenvironment (TME) in cancer has improved our understanding of cancer immunology, but complex spatial analyses of tumor-immune interactions in lymphoma are lacking. From this plot, it is apparent that these four data points have high cell and nuclear area (two left-most coordinates) but low cell count (right-most coordinate). The four selected blue data points in the scatterplot are also highlighted in the parallel coordinate plot as blue lines. (d) Parallel coordinate plot where 6 features are plotted, one on each numbered axis as labeled in the table shown below the plot. (c) Density plot of individual cell data (X-axis = area of the cell Y-axis = area of the nucleus. One particular sample and its replicates are highlighted as blue data points, and the blue lines indicate +/- two standard deviations from the mean, although because the data is non-Gaussian, the left standard deviation line is not visible.

(b) Scatterplot of image data (X-axis = mean area of all cells in the image Y-axis = mean area of all nuclei in the image). (a) A histogram of per-image data (the mean area of all cells in the image). Four types of plots created by CellProfiler Analyst are shown.

Download cellprofiler analyst software 64 bit