Recent clinical successes of cancer immunotherapy necessitate the investigation of the interaction between malignant cells and the host immune system. However, elucidation of complex tumor-immune interactions presents major computational and experimental challenges. Here we present Tumor Immune Estimation Resource (TIMER, cistrome.shinyapps.io/timer) to comprehensively investigate molecular characterization of tumor-immune interactions. Levels of six tumor-infiltrating immune subsets are pre-calculated for 10,897 tumors from 32 cancer types. TIMER provides 6 major analytic modules that allow users to interactively explore the associations between immune infiltrates and a wide-spectrum of factors, including gene expression, clinical outcomes, somatic mutations, and somatic copy number alterations. TIMER provides a user-friendly web interface for dynamic analysis and visualization of these associations, which will be of broad utilities to cancer researchers.

Cancer results from a breakdown of normal gene expression control, so the study of gene regulation is critical to cancer research. To gain insight into the transcriptional and epigenetic factors regulating abnormal gene expression patterns in cancers, we developed the Cistrome Cancer web resource (http://cistrome.org/CistromeCancer/). We conducted the systematic integration and modeling of over ten thousand tumor molecular profiles from The Cancer Genome Atlas (TCGA) with over twenty-three thousand ChIP-seq and chromatin accessibility profiles from our Cistrome collection. The results include reconstruction of functional enhancer profiles, “super-enhancer” target genes, as well as predictions of active transcription factors (TF) and their target genes for each TCGA cancer type. Cistrome Cancer reveals novel insights from integrative analyses combining chromatin profiles with tumor molecular profiles, and will be a useful resource to the cancer gene regulation community.

Highlights d Synthetic lethal and resistance interactions with BET inhibitors in TNBC d Multiple independent unbiased screens identify the same genes and pathways d CDK4/6 inhibitors and paclitaxel have top synergies with BET bromodomain inhibitors d Deletion of SNF/SWI complex components leads to BET inhibitor resistance

Neoantigen-specific tumor-infiltrating Tlymphocytes are immune effector cells for cancer elimination and are the primary focus of current cancer immunotherapies [1][2][3][4] . We previously published a novel method to assemble T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences using paired-end tumor RNA-seq data 5 . Extending this approach, we have developed 'TCR repertoire utilities for solid tissue', or TRUST, for ultrasensitive detection of tumor-infiltrating T cell CDR3 sequences (Supplementary Software). TRUST significantly outperforms our previous method, with a substantial increase in recall (Supplementary Fig. 1a), especially for libraries with deeper coverage and longer read length (Supplementary Fig. 1b). In addition to exhibiting improved performance, TRUST can also handle single-end RNA-seq data and has demonstrated utility for noncancerous tissues.TRUST takes single-end or paired-end library reads mapped to the human reference genome in BAM format as the standard input. It automatically detects input library type, selects informative unmapped reads, assigns reads into TCR genes on the basis of putative motifs, assembles reads into contigs and annotates the assembled CDR3 sequences with

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood. We carried out ultra-deep profiling of indels and systematically dissected the underlying mechanisms using passenger-immunoglobulin mouse models. We found that activation-induced cytidine deaminase–dependent ±1–base pair (bp) indels are the most prevalent indel events, biasing deleterious outcomes, whereas longer in-frame indels, especially insertions that can extend the CDR3 length, are rare outcomes. The ±1-bp indels are channeled by base excision repair, but longer indels require additional DNA-processing factors. Ectopic expression of a DNA exonuclease or perturbation of the balance of DNA polymerases can increase the frequency of longer indels, thus paving the way for models that can generate antibodies with long CDR3. Our study reveals the mechanisms that generate beneficial and deleterious indels during the process of antibody somatic hypermutation and has implications in understanding the detrimental genomic alterations in various conditions, including tumorigenesis.