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Mar 2023 • Ophthalmic Technologies XXXIII, PC123600Z, 2023

Binocular varichroma and accommodation measurement system: the visual impact of LCA or TCA correction

Derek Nankivil, Swati Bhargava, Nadav H Ivzan, Steven A Cholewiak, Francesco LaRocca, Austin Roorda, Martin S Banks

Longitudinal chromatic aberration (LCA) and transverse chromatic aberration (TCA) adversely affect retinal image quality. Thus, one expects improved visual performance when chromatic aberrations are minimized or eliminated. Systematic evaluation of the impact of LCA and/or TCA correction under broadband illumination is needed. Thus, we developed a system, called the Binocular Varichroma and Accommodation Measurement System (BVAMS) that can be used to measure and correct the eye’s LCA and TCA and to perform vision tests with custom corrections. We demonstrate a measurable benefit in visual acuity only with both LCA and TCA correction.

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Mar 2023 • Blood cancer discovery

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Elisa Ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A Redd, Neil Ruthen, Sébastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M Parry, Julien Broséus, Romain Guieze, Fabienne Lucas, María Hernández-Sánchez, Kaitlyn Baranowski, Jackson Southard, Heather Joyal, Leah Billington, Fara Faye D Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S Davids, Gad Getz, Kenneth J Livak, Ivana Bozic, Donna S Neuberg, Ruben D Carrasco, Catherine J Wu

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN …

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Mar 2023 • Cancer Research

Mitochondrial DNA mutations as natural barcodes for lineage tracing of murine tumor models

Livius Penter, Elisa Ten Hacken, Jackson Southard, Caleb A Lareau, Leif S Ludwig, Shuqiang Li, Donna S Neuberg, Kenneth J Livak, Catherine J Wu

Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize …

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Mar 2023 • Blood Cancer Discovery

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Elisa Ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A Redd, Neil Ruthen, Sébastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M Parry, Julien Broséus, Romain Guieze, Fabienne Lucas, María Hernández-Sánchez, Kaitlyn Baranowski, Jackson Southard, Heather Joyal, Leah Billington, Fara Faye D Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S Davids, Gad Getz, Kenneth J Livak, Ivana Bozic, Donna S Neuberg, Ruben D Carrasco, Catherine J Wu

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN …

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Feb 2023 • Journal of Vision

The visual benefits of correcting longitudinal and transverse chromatic aberration

Austin Roorda, Steven A Cholewiak, Swati Bhargava, Nadav H Ivzan, Francesco LaRocca, Derek Nankivil, Martin S Banks

We describe a system—the Binocular Varichrome and Accommodation Measurement System—that can be used to measure and correct the eye’s longitudinal and transverse chromatic aberration (LCA and TCA) and to perform vision tests with custom corrections. We used the system to investigate how LCA and TCA affect visual performance. Specifically, we studied the effects of LCA and TCA on visual acuity, contrast sensitivity, and chromostereopsis. LCA exhibited inter subject variability but followed expected trends compared with previous reports. TCA at the fovea was variable between individuals but with a tendency for the shift at shorter wavelengths to be more temporalward in the visual field in each eye. We found that TCA was generally greater when LCA was corrected. For visual acuity, we found that a measurable benefit was realized only with both LCA and TCA correction unless the TCA was low. For contrast sensitivity, we found that the best sensitivity to a 10-cycle/degree polychromatic grating was attained when LCA and TCA were corrected. Finally, we found that the primary cause of chromostereopsis is the TCA of the eyes.

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Feb 2023 • Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy

Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic GvHD and Candidate Gvl Targets

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Jonathan Stevens, Kameron Kooshesh, Helen Ji, Susan Klaeger, Karl R Clauser, Siranush Sarkizova, David A Braun, Livius Penter, Giacomo Oliveira, Haesook T Kim, William J Lane, Shuqiang Li, Kenneth J Livak, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Derin B Keskin, Chip Stewart, Alexander Gusev, Gad Getz, Catherine J Wu

At the core of the therapeutic effect of HLA-matched allo-HCT is T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient disparity at sites of single nucleotide polymorphisms (SNPs). Despite their crucial role in GvL and GvHD, only few mHAgs have been characterized to date. To systematically identify autosomal and Y chromosome-encoded mHAgs, we devised a computational pipeline based on: i) comparison of whole exomes (WES) from donor-recipient pairs to define recipient-restricted exonic non-synonymous SNPs; ii) expression filters built by incorporating the analysis of single-cell RNA expression profiles from normal and malignant hematopoietic cells, and GvHD target organs (skin, liver, GI, lung, oral mucosa and lacrimal gland). Identified recipient-restricted SNPs, expressed in GvL or GvHD tissues, then underwent HLA-I binding prediction …

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Feb 2023 • Journal of Vision

The visual benefits of correcting longitudinal and transverse chromatic aberration

Austin Roorda, Steven A Cholewiak, Swati Bhargava, Nadav H Ivzan, Francesco LaRocca, Derek Nankivil, Martin S Banks

We describe a system—the Binocular Varichrome and Accommodation Measurement System—that can be used to measure and correct the eye’s longitudinal and transverse chromatic aberration (LCA and TCA) and to perform vision tests with custom corrections. We used the system to investigate how LCA and TCA affect visual performance. Specifically, we studied the effects of LCA and TCA on visual acuity, contrast sensitivity, and chromostereopsis. LCA exhibited inter subject variability but followed expected trends compared with previous reports. TCA at the fovea was variable between individuals but with a tendency for the shift at shorter wavelengths to be more temporalward in the visual field in each eye. We found that TCA was generally greater when LCA was corrected. For visual acuity, we found that a measurable benefit was realized only with both LCA and TCA correction unless the TCA was low. For contrast sensitivity, we found that the best sensitivity to a 10-cycle/degree polychromatic grating was attained when LCA and TCA were corrected. Finally, we found that the primary cause of chromostereopsis is the TCA of the eyes.

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Jan 2023 • Cancer discovery

A molecular switch between mammalian MLL complexes dictates response to Menin–MLL inhibition

Yadira M Soto-Feliciano, Francisco J Sánchez-Rivera, Florian Perner, Douglas W Barrows, Edward R Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X Shirley Liu, Andrei V Krivtsov, Maximiliano Meneses, Elisa de Stanchina, Richard M Stone, Scott A Armstrong, Scott W Lowe, C David Allis

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1–Menin and MLL3/4–UTX chromatin-modifying complexes that dictates response to Menin–MLL inhibitors. MLL1–Menin safeguards leukemia survival by impeding the binding of the MLL3/4–UTX complex at a subset of target gene promoters. Disrupting the Menin–MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are …

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Jan 2023 • Blood Journal

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease

Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole Cullen, Kathleen Lindahl Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna Neuberg, F Stephen Hodi, Sacha Gnjatic, Matthew S Davids, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

The challenge of eradicating leukemia for patients with acute myelogenous leukemia (AML) following initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 (NCT02890329) study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either following allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304,961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent following ipilimumab …

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Dec 2022 • Cancer Research

Mitochondrial DNA mutations as natural barcodes for lineage tracing of murine tumor models

Livius Penter, Elisa ten Hacken, Jackson Southard, Caleb Lareau, Leif S Ludwig, Shuqiang Li, Donna S Neuberg, Kenneth J Livak, Catherine J Wu

Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize murine cancer models.

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Dec 2022 • Cancer Immunology Research

Abstract B65: MetaTiME: meta-components of the tumor immune microenvironment

Yi Zhang, Guanjue Xiang, Yijia Alva Jiang, Allen Lynch, Zexian Zeng, Chenfei Wang, Wubing Zhang, Jingyu Fan, Jiajinlong Kang, Shengqing Gu, Changxin Wan, Boning Zhang, Shirley Liu, Myles Brown, Clifford Meyer

Recent advances in single-cell RNA sequencing have revealed heterogeneous cell types and gene expression states in the non-cancerous cells in tumors. The integration of multiple scRNA-seq datasets across tumors can reveal common cell types and states in the tumor microenvironment (TME). However, tumor scRNA analysis relies on clustering cells and annotating with markers from experts. Subsequent challenges include inconsistent cell type and state definition, different marker usage among studies, and that clustering doesn’t find continuous cell states. We developed a data-driven framework, MetaTiME, to overcome the limitations in resolution and consistency that result from manual labeling using known gene markers. Using millions of TME single cells, MetaTiME learns meta-components that encode independent components of gene expression observed across cancer types. The meta-components are …

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Dec 2022 • Cancer Immunology Research

Hippo Signaling Pathway Regulates Cancer Cell–Intrinsic MHC-II Expression

Zexian Zeng, Shengqing Stan Gu, Nofal Ouardaoui, Carly Tymm, Lin Yang, Cheryl J Wong, Dian Li, Wubing Zhang, Xiaoqing Wang, Jason L Weirather, Scott J Rodig, F Stephen Hodi, Myles Brown, X Shirley Liu

MHC-II is known to be mainly expressed on the surface of antigen-presenting cells. Evidence suggests MHC-II is also expressed by cancer cells and may be associated with better immunotherapy responses. However, the role and regulation of MHC-II in cancer cells remain unclear. In this study, we leveraged data mining and experimental validation to elucidate the regulation of MHC-II in cancer cells and its role in modulating the response to immunotherapy. We collated an extensive collection of omics data to examine cancer cell–intrinsic MHC-II expression and its association with immunotherapy outcomes. We then tested the functional relevance of cancer cell–intrinsic MHC-II expression using a syngeneic transplantation model. Finally, we performed data mining to identify pathways potentially involved in the regulation of MHC-II expression, and experimentally validated candidate regulators …

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Nov 2022 • Cancer Immunology Research

Immune phenotypes and target antigens of clonally expanded bone marrow T cells in treatment-naïve multiple myeloma

Carlotta Welters, María Fernanda Lammoglia Cobo, Christian Alexander Stein, Meng-Tung Hsu, Amin Ben Hamza, Livius Penter, Xiaojing Chen, Christopher Buccitelli, Oliver Popp, Philipp Mertins, Kerstin Dietze, Lars Bullinger, Andreas Moosmann, Eric Blanc, Dieter Beule, Armin Gerbitz, Julian Strobel, Holger Hackstein, Hans-Peter Rahn, Klaus Dornmair, Thomas Blankenstein, Leo Hansmann

Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiological relevance, the roles of bone marrow infiltrating T cells in treatment-naïve patients are incompletely understood. We investigated whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow, ii) showed characteristic immune phenotypes, and iii) whether dominant clones recognized antigens selectively presented on multiple myeloma cells. Single-cell index sorting and T-cell receptor (TCR)αβ sequencing of bone marrow T cells from 13 treatment-naïve patients showed dominant clonal expansion within CD8+ cytolytic effector compartments, and only a minority of expanded T-cell clones expressed the classical immune checkpoint molecules PD 1, CTLA 4, or TIM 3. To identify their molecular targets, TCRs of 68 dominant bone marrow clones from five selected patients were re-expressed and incubated with multiple myeloma and non multiple myeloma cells from corresponding patients. Only one out of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C-restricted, self-peptide-specific, and could be activated by multiple myeloma cells of multiple patients. The remaining dominant T-cell clones did not recognize multiple myeloma cells and were, in part, specific for antigens associated with chronic viral infections. In conclusion, we showed that dominant bone marrow T-cell clones in treatment naïve patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classical immune checkpoint …

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Nov 2022 • Blood

Mechanisms of Response and Resistance to Combination Decitabine and Ipilimumab for Transplant Naïve and Post-Transplant AML/MDS

Livius Penter, Yang Liu, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Jacquelyn Wolff, Nicole Cullen, Kathleen Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Helen Chen, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Jerome Ritz, Howard Streicher, Donna S Neuberg, Stephen Hodi, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Treatment of patients with advanced myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) ineligible for intensive chemotherapy currently is mostly non-curative and therapeutic options for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) rarely induce durable remissions. Novel strategies to address disease relapse are thus needed. Immune checkpoint blockade with CTLA-4 antibodies (ipilimumab) is an emerging concept that demonstrated potent clinical activity in relapsed leukemia cutis post-HSCT. Hypothesizing synergism with therapeutic hypomethylation, the ETCTN/CTEP study 10026 evaluated the safety and efficacy of combination decitabine and ipilimumab treatment in transplant-naïve AML/MDS and post-HSCT AML relapse (NCT02890329). Clinical activity has been encouraging with an overall response rate of 20%(post-HSCT) and 52%(transplant-naïve), however …

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Nov 2022 • Blood

Ipilimumab plus decitabine for patients with MDS or AML in post-transplant or transplant naïve settings

Jacqueline S Garcia, Yael Flamand, Livius Penter, Michael Keng, Benjamin K Tomlinson, Lourdes M Mendez, Paul Koller, Nicole Cullen, Yohei Arihara, Kathleen Pfaff, Jacquelyn O Wolff, Andrew M Brunner, Ilene Galinsky, Asad Bashey, Joseph H Antin, Corey Cutler, Vincent Ho, Brian A Jonas, Marlise R Luskin, Martha Wadleigh, Eric S Winer, Alexandra Savell, Rebecca Leonard, Taylor Robertson, Matthew S Davids, Howard Streicher, Scott J Rodig, Jerome Ritz, Catherine J Wu, Daniel J DeAngelo, Donna Neuberg, Richard M Stone, Robert J Soiffer

Ipilimumab monotherapy has clinical activity in patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic stem cell transplant (HSCT) when disease burden is low. We hypothesized that ipilimumab-driven responses required alloreactivity and the addition of decitabine could augment responses without generating excessive toxicity. We conducted a multicenter phase 1 trial of ipilimumab and decitabine (IPI+ DEC) in relapsed, refractory or secondary untreated MDS/AML (CTEP10026; NCT02890329) with patients stratified by transplant status. Patients received a lead-in cycle of decitabine followed by combination therapy with IPI (3, 5, or 10 mg/kg) every 4 weeks for four cycles and then every 8 weeks for up to eight cycles. In total, 48 patients received IPI+ DEC (25 post-HSCT, 23 transplant naïve). In the post-HSCT cohort, 36%(9/25) experienced immune-related adverse events (irAEs …

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Nov 2022 • Blood

Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic Gvhd and Candidate GVL Targets

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Jonathan Stevens, Kameron Kooshesh, Susan Klaeger, Karl R Clauser, Siranush Sarkizova, David A Braun, Livius Penter, Giacomo Oliveira, Haesook T Kim, William J Lane, Shuqiang Li, Kenneth J Livak, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Derin B Keskin, Chip Stewart, Alexander Gusev, Gad Getz, Catherine J Wu

At the core of the therapeutic effect of HLA-matched allogeneic hematopoietic cell transplantation (allo-HCT) is T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient disparity at sites of single nucleotide gene polymorphisms (SNPs). Despite their crucial role in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD), only few mHAgs have been characterized to date.

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Oct 2022 • Science Advances

Machine learning on syngeneic mouse tumor profiles to model clinical immunotherapy response

Zexian Zeng, Shengqing Stan Gu, Cheryl J Wong, Lin Yang, Nofal Ouardaoui, Dian Li, Wubing Zhang, Myles Brown, X Shirley Liu

Most patients with cancer are refractory to immune checkpoint blockade (ICB) therapy, and proper patient stratification remains an open question. Primary patient data suffer from high heterogeneity, low accessibility, and lack of proper controls. In contrast, syngeneic mouse tumor models enable controlled experiments with ICB treatments. Using transcriptomic and experimental variables from >700 ICB-treated/control syngeneic mouse tumors, we developed a machine learning framework to model tumor immunity and identify factors influencing ICB response. Projected on human immunotherapy trial data, we found that the model can predict clinical ICB response. We further applied the model to predicting ICB-responsive/resistant cancer types in The Cancer Genome Atlas, which agreed well with existing clinical reports. Last, feature analysis implicated factors associated with ICB response. In summary, our …

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Sep 2022 • Blood, The Journal of the American Society of Hematology

AML relapse after a TIGIT race

Livius Penter, Catherine J Wu

In this issue of Blood, Gournay et al 1 dissect donor immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) with mass cytometry and identify T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD161-expressing CD4+ T cells as early immune correlates of subsequent acute myelogenous leukemia (AML) relapse after HSCT.The high relapse rate of AML after stem cell transplant has remained one of the most tenacious problems in malignant hematology. With the graft-versusleukemia (GVL) effect at the core of successful long-term disease control, the early posttransplant course can be thought of as a delicate race between nascent donor immune reconstitution and recovering malignant cell populations that seek to escape GVL. AML relapse after HSCT thus often associates with donor immune cell dysfunction through upregulated immune checkpoint molecules or reduced …

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Sep 2022 • Nature Methods

MIRA: joint regulatory modeling of multimodal expression and chromatin accessibility in single cells

Allen W Lynch, Christina V Theodoris, Henry W Long, Myles Brown, X Shirley Liu, Clifford A Meyer

Rigorously comparing gene expression and chromatin accessibility in the same single cells could illuminate the logic of how coupling or decoupling of these mechanisms regulates fate commitment. Here we present MIRA, probabilistic multimodal models for integrated regulatory analysis, a comprehensive methodology that systematically contrasts transcription and accessibility to infer the regulatory circuitry driving cells along cell state trajectories. MIRA leverages topic modeling of cell states and regulatory potential modeling of individual gene loci. MIRA thereby represents cell states in an efficient and interpretable latent space, infers high-fidelity cell state trees, determines key regulators of fate decisions at branch points and exposes the variable influence of local accessibility on transcription at distinct loci. Applied to epidermal differentiation and embryonic brain development from two different multimodal …

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Sep 2022 • Blood, The Journal of the American Society of Hematology

AML relapse after a TIGIT race

Livius Penter, Catherine J Wu

In this issue of Blood, Gournay et al 1 dissect donor immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) with mass cytometry and identify T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD161-expressing CD4+ T cells as early immune correlates of subsequent acute myelogenous leukemia (AML) relapse after HSCT.The high relapse rate of AML after stem cell transplant has remained one of the most tenacious problems in malignant hematology. With the graft-versusleukemia (GVL) effect at the core of successful long-term disease control, the early posttransplant course can be thought of as a delicate race between nascent donor immune reconstitution and recovering malignant cell populations that seek to escape GVL. AML relapse after HSCT thus often associates with donor immune cell dysfunction through upregulated immune checkpoint molecules or reduced …

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Sep 2022 • Cancer Immunology Research

Immune phenotypes and target antigens of clonally expanded bone marrow T cells in treatment-naïve multiple myeloma

Carlotta Welters, Lammoglia Cobo MF, Christian Alexander Stein, Meng Tung Hsu, L Penter, X Chen, C Buccitelli, O Popp, P Mertins, K Dietze, L Bullinger, A Moosmann, E Blanc, D Beule, A Gerbitz, J Strobel, H Hackstein, HP Rahn, K Dornmair, T Blankenstein, L Hansmann


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