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Sep 2021 • Cell

In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target

Xiaoqing Wang, Collin Tokheim, Shengqing Stan Gu, Binbin Wang, Qin Tang, Yihao Li, Nicole Traugh, Zexian Zeng, Yi Zhang, Ziyi Li, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford A Meyer, Jun Chu, Peng Jiang, Paloma Cejas, Klothilda Lim, Henry Long, Myles Brown, X Shirley Liu

Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated …

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Sep 2021 • Cell

In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target

Xiaoqing Wang, Collin Tokheim, Shengqing Stan Gu, Binbin Wang, Qin Tang, Yihao Li, Nicole Traugh, Zexian Zeng, Yi Zhang, Ziyi Li, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford A Meyer, Jun Chu, Peng Jiang, Paloma Cejas, Klothilda Lim, Henry Long, Myles Brown, X Shirley Liu

Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated …

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Sep 2021 • Cell

In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target

Xiaoqing Wang, Collin Tokheim, Shengqing Stan Gu, Binbin Wang, Qin Tang, Yihao Li, Nicole Traugh, Zexian Zeng, Yi Zhang, Ziyi Li, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford A Meyer, Jun Chu, Peng Jiang, Paloma Cejas, Klothilda Lim, Henry Long, Myles Brown, X Shirley Liu

Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated …

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Aug 2021 • Blood Advances

Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case

Livius Penter, Satyen H Gohil, Teddy Huang, Emily M Thrash, Dominik Schmidt, Shuqiang Li, Mariano Severgnini, Donna Neuberg, F Stephen Hodi, Kenneth J Livak, Robert Zeiser, Pavan Bachireddy, Catherine J Wu

Relapse of myeloproliferative neoplasms (MPN) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with poor outcomes, as therapeutic approaches to reinstate effective graft-versus-leukemia (GvL) responses remain suboptimal. Immune escape through overexpression of PD-L1 in JAK2V617F mutated MPN provides a rationale for therapeutic PD-1 blockade, and indeed clinical activity of nivolumab in relapsed MPN post-HSCT has been observed. Elucidation of the features of response following PD-1 blockade in such patients could inform of novel therapeutic concepts for how to enhance GvL. Here, we report an integrated high-dimensional analysis using single cell RNA-, TCR-, CITE- and ATAC-sequencing together with mass cytometry on peripheral blood mononuclear cells collected at 6 timepoints before, during and after transient response to PD-1 blockade from an index case of …

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Aug 2021 • Genomics, Proteomics and Bioinformatics

CoBRA: containerized bioinformatics workflow for reproducible ChIP/ATAC-seq analysis

Xintao Qiu, Avery S Feit, Ariel Feiglin, Yingtian Xie, Nikolas Kesten, Len Taing, Joseph Perkins, Shengqing Gu, Yihao Li, Paloma Cejas, Ningxuan Zhou, Rinath Jeselsohn, Myles Brown, X Shirley Liu, Henry W Long

Chromatin immunoprecipitation sequencing (ChIP-seq) and the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) have become essential technologies to effectively measure protein–DNA interactions and chromatin accessibility. However, there is a need for a scalable and reproducible pipeline that incorporates proper normalization between samples, correction of copy number variations, and integration of new downstream analysis tools. Here we present Containerized Bioinformatics workflow for Reproducible ChIP/ATAC-seq Analysis (CoBRA), a modularized computational workflow which quantifies ChIP-seq and ATAC-seq peak regions and performs unsupervised and supervised analyses. CoBRA provides a comprehensive state-of-the-art ChIP-seq and ATAC-seq analysis pipeline that can be used by scientists with limited computational experience. This enables …

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Jul 2021 • AACR Annual Meeting 2021, 2021

Abstract 65: Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade

Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L. Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, Myles Brown and X. Shirley Liu


Jun 2021 • Blood, The Journal of the American Society of Hematology

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

Livius Penter, Yi Zhang, Alexandra Savell, Teddy Huang, Nicoletta Cieri, Emily M Thrash, Seunghee Kim-Schulze, Aashna Jhaveri, Jingxin Fu, Srinika Ranasinghe, Shuqiang Li, Wandi Zhang, Emma S Hathaway, Matthew Nazzaro, Haesook T Kim, Helen Chen, Magdalena Thurin, Scott J Rodig, Mariano Severgnini, Carrie Cibulskis, Stacey Gabriel, Kenneth J Livak, Corey Cutler, Joseph H Antin, Sarah Nikiforow, John Koreth, Vincent T Ho, Philippe Armand, Jerome Ritz, Howard Streicher, Donna Neuberg, F Stephen Hodi, Sacha Gnjatic, Robert J Soiffer, X Shirley Liu, Matthew S Davids, Pavan Bachireddy, Catherine J Wu

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell …

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Jun 2021 • Nat Methods

TRUST4: immune repertoire reconstruction from bulk and single-cell RNA-seq data

Liu XS Song L, Cohen D, Ouyang Z, Cao Y, Hu X

We introduce the TRUST4 open-source algorithm for reconstruction of immune receptor repertoires in αβ/γδ T cells and B cells from RNA-sequencing (RNA-seq) data. Compared with competing methods, TRUST4 supports both FASTQ and BAM format and is faster and more sensitive in assembling longer—even full-length—receptor repertoires. TRUST4 can also call repertoire sequences from single-cell RNA-seq (scRNA-seq) data without V (D) J enrichment, and is compatible with both SMART-seq and 5′ 10x Genomics platforms.

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May 2021 • Nature Machine Intelligence

Neural network architecture search with AMBER

Yi Zhang, Yang Liu, X Shirley Liu

Deep learning has been powerful in learning complex functions from data and has been applied in computer vision, natural language processing and biology. If we view the human genome as a book with three billion letters of nucleotides represented by A, C, G and T, genes and gene-controlling sequences are encoded in the book and variations in the genome can link to disease conditions. Neural network models that extract patterns from the sequences can help predict functional genomic elements and interpret genetic variations. However, the current deep learning models for genomics usually involve expert-designed neural network structures and require extensive tuning, making such models unapproachable for most other scientists. In a recent publication in Nature Machine Intelligence, Zhang and colleagues 1 present a framework called Automated Modelling for Biological Evidence-based Research …

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May 2021 • Nature Machine Intelligence

Neural network architecture search with AMBER

Yi Zhang, Yang Liu, X Shirley Liu

Deep learning applied to genomics can learn patterns in biological sequences, but designing such models requires expertise and effort. Recent work demonstrates the efficiency of a neural network architecture search algorithm in optimizing genomic models.

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Apr 2021 • Neuro-oncology

Functional analysis of low-grade glioma genetic variants predicts key target genes and transcription factors

Mohith Manjunath, Jialu Yan, Yeoan Youn, Kristen L Drucker, Thomas M Kollmeyer, Andrew M McKinney, Valter Zazubovich, Yi Zhang, Joseph F Costello, Jeanette Eckel-Passow, Paul R Selvin, Robert B Jenkins, Jun S Song

Background Large-scale genome-wide association studies (GWAS) have implicated thousands of germline genetic variants in modulating individuals’ risk to various diseases, including cancer. At least 25 risk loci have been identified for low-grade gliomas (LGGs), but their molecular functions remain largely unknown. Methods We hypothesized that GWAS loci contain causal single nucleotide polymorphisms (SNPs) that reside in accessible open chromatin regions and modulate the expression of target genes by perturbing the binding affinity of transcription factors (TFs). We performed an integrative analysis of genomic and epigenomic data from The Cancer Genome Atlas and other public repositories to identify candidate causal SNPs within linkage disequilibrium blocks of LGG GWAS loci. We assessed their potential regulatory role via in silico TF binding sequence …

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Mar 2021 • Cell

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

Nathan D Mathewson, Orr Ashenberg, Itay Tirosh, Simon Gritsch, Elizabeth M Perez, Sascha Marx, Livnat Jerby-Arnon, Rony Chanoch-Myers, Toshiro Hara, Alyssa R Richman, Yoshinaga Ito, Jason Pyrdol, Mirco Friedrich, Kathrin Schumann, Michael J Poitras, Prafulla C Gokhale, L Nicolas Gonzalez Castro, Marni E Shore, Christine M Hebert, Brian Shaw, Heather L Cahill, Matthew Drummond, Wubing Zhang, Olamide Olawoyin, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Priscilla K Brastianos, X Shirley Liu, Pamela S Jones, Daniel P Cahill, Matthew P Frosch, David N Louis, Gordon J Freeman, Keith L Ligon, Alexander Marson, E Antonio Chiocca, David A Reardon, Aviv Regev, Mario L Suvà, Kai W Wucherpfennig

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by …

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Mar 2021 • Optics Express

Optimal allocation of quantized human eye depth perception for multi-focal 3D display design

Alireza Aghasi, Barmak Heshmat, Leihao Wei, Moqian Tian

Creating immersive 3D stereoscopic, autostereoscopic, and lightfield experiences are becoming the center point of optical design of future head mounted displays and lightfield displays. However, despite the advancement in 3D and light field displays, there is no consensus on what are the necessary quantized depth levels for such emerging displays at stereoscopic or monocular modalities. Here we start from psychophysical theories and work toward defining and prioritizing quantized levels of depth that would saturate the human depth perception. We propose a general optimization framework, which locates the depth levels in a globally optimal way for band limited displays. While the original problem is computationally intractable, we manage to find a tractable reformulation as maximally covering a region of interest with a selection of hypographs corresponding to the monocular depth of field profiles. The results …

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Mar 2021 • Journal of vision

Lags and leads of accommodation in humans: Fact or fiction?

Vivek Labhishetty, Steven A Cholewiak, Austin Roorda, Martin S Banks

The focusing response of the human eye—accommodation—exhibits errors known as lags and leads. Lags occur when the stimulus is near and the eye appears to focus farther than the stimulus. Leads occur with far stimuli where the eye appears to focus nearer than the stimulus. We used objective and subjective measures simultaneously to determine where the eye is best focused. The objective measures were made with a wavefront sensor and an autorefractor, both of which analyze light reflected from the retina. These measures exhibited typical accommodative errors, mostly lags. The subjective measure was visual acuity, which of course depends not only on the eye’s optics but also on photoreception and neural processing of the retinal image. The subjective measure revealed much smaller errors. Acuity was maximized at or very close to the distance of the accommodative stimulus. Thus, accommodation is accurate in terms of maximizing visual performance.

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Feb 2021 • Molecular Cell

Systematic characterization of mutations altering protein degradation in human cancers

Collin Tokheim, Xiaoqing Wang, Richard T Timms, Boning Zhang, Elijah L Mena, Binbin Wang, Cynthia Chen, Jun Ge, Jun Chu, Wubing Zhang, Stephen J Elledge, Myles Brown, X Shirley Liu

The ubiquitin-proteasome system (UPS) is the primary route for selective protein degradation in human cells. The UPS is an attractive target for novel cancer therapies, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes affect UPS function. We implicate transcription factors as important substrates and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Last, we identified UPS driver genes associated with prognosis and the tumor microenvironment. This study demonstrates the …

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Jan 2021 • Clinical Cancer Research

Network for biomarker immunoprofiling for cancer immunotherapy: Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC)

Helen X Chen, Minkyung Song, Holden T Maecker, Sacha Gnjatic, David Patton, J Jack Lee, Stacey J Adam, Radim Moravec, X Shirley Liu, Ethan Cerami, James Lindsay, F Stephen Hodi, Catherine Wu, Ignacio I Wistuba, Gheath Al-Atrash, Chantale Bernatchez, Sean C Bendall, Stephen M Hewitt, Elad Sharon, Howard Streicher, Rebecca A Enos, Melissa D Bowman, Valerie M Tatard-Leitman, Beatriz Sanchez-Espiridion, Srinika Ranasinghe, Mina Pichavant, Diane M Del Valle, Joyce Yu, Sylvie Janssens, Jenny Peterson-Klaus, Cathy Rowe, Gerold Bongers, Robert R Jenq, Chia-Chi Chang, Jeffrey S Abrams, Margaret Mooney, James H Doroshow, Lyndsay N Harris, Magdalena Thurin

Immunoprofiling to identify biomarkers and integration with clinical trials outcome are critical to improve immunotherapy approaches for cancer patients. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assays further limits comparison and interpretation of data across studies and laboratories. To enable a systematic approach to biomarker identification and correlation with clinical outcome across trials, the Cancer Immune Monitoring and Analysis Centers and Cancer Immunologic Data Commons (CIMAC-CIDC) Network was established through support of the Cancer MoonshotSM Initiative of the National Cancer Institute and the Partnership for Accelerating Cancer Therapies (PACT) with industry partners via the Foundation for the National Institutes of Health. The CIMAC-CIDC Network is composed …

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Jan 2021 • Cancer Discovery

Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade

Shengqing Stan Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael P Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok K Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J Freeman, Scott Rodig, Henry W Long, Benjamin E Gewurz, F Stephen Hodi, Myles Brown, X Shirley Liu

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell–dependent killing, and adds to ICB efficacy. Our findings provide …

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Jan 2021 • Cancer Discovery

CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor cells and T cells

Sushil Kumar, Zexian Zeng, Archis Bagati, Rong En Tay, Lionel A Sanz, Stella R Hartono, Yoshinaga Ito, Fieda Abderazzaq, Elodie Hatchi, Peng Jiang, Adam NR Cartwright, Olamide Olawoyin, Nathan D Mathewson, Jason W Pyrdol, Mamie Z Li, John G Doench, Matthew A Booker, Michael Y Tolstorukov, Stephen J Elledge, Frederic Chedin, X Shirley Liu, Kai W Wucherpfennig

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors …

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Jan 2021 • bioRxiv

Leveraging epigenomes and three-dimensional genome organization for interpreting regulatory variation

Brittany Anne Baur, Junha Shin, Jacob Schreiber, Shilu Zhang, Yi Zhang, Mohith Manjunath, Jun S Song, William Stafford Noble, Sushmita Roy

Understanding the impact of regulatory variants on complex phenotypes is a significant challenge because the genes and pathways that are targeted by such variants are typically unknown. Furthermore, a regulatory variant might influence a particular gene9s expression in a cell type or tissue-specific manner. Cell-type specific long-range regulatory interactions that occur between a distal regulatory sequence and a gene offers a powerful framework for understanding the impact of regulatory variants on complex phenotypes. However, high-resolution maps of such long-range interactions are available only for a handful of model cell lines. To address this challenge, we have developed L-HiC-Reg, a Random Forests based regression method to predict high-resolution contact counts in new cell lines, and a network-based framework to identify candidate cell line-specific gene networks targeted by a set of variants from a Genome-wide association study (GWAS). We applied our approach to predict interactions in 55 Roadmap Epigenome Consortium cell lines, which we used to interpret regulatory SNPs in the NHGRI GWAS catalogue. Using our approach, we performed an in-depth characterization of fifteen different phenotypes including Schizophrenia, Coronary Artery Disease (CAD) and Crohn9s disease. In CAD, we found differentially wired subnetworks consisting of known as well as novel gene targets of regulatory SNPs. Taken together, our compendium of interactions and associated network-based analysis pipeline offers a powerful resource to leverage long-range regulatory interactions to examine the context-specific impact of regulatory …

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Jan 2021 • Cancer Cell

Integrin αvβ6–TGFβ–SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer

Archis Bagati, Sushil Kumar, Peng Jiang, Jason Pyrdol, Angela E Zou, Anze Godicelj, Nathan D Mathewson, Adam NR Cartwright, Paloma Cejas, Myles Brown, Anita Giobbie-Hurder, Deborah Dillon, Judith Agudo, Elizabeth A Mittendorf, X Shirley Liu, Kai W Wucherpfennig

Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ …

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Jan 2021 • Cancer Discovery

CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor cells and T cells

Sushil Kumar, Zexian Zeng, Archis Bagati, Rong En Tay, Lionel A Sanz, Stella R Hartono, Yoshinaga Ito, Fieda Abderazzaq, Elodie Hatchi, Peng Jiang, Adam NR Cartwright, Olamide Olawoyin, Nathan D Mathewson, Jason W Pyrdol, Mamie Z Li, John G Doench, Matthew A Booker, Michael Y Tolstorukov, Stephen J Elledge, Frederic Chedin, X Shirley Liu, Kai W Wucherpfennig

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme and co-transcriptional activator, elicited beneficial anti-tumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their anti-tumor function and preserved memory-like populations required for sustained anti-tumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells and NK cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of Carm1 with a small molecule elicited potent anti-tumor immunity and sensitized resistant tumors to checkpoint blockade …

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