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Aug 2024 • The Journal of Clinical Investigation

Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti–TIM-3 therapy in mice

Nana Talvard-Balland, Lukas M Braun, Karen O Dixon, Melissa Zwick, Helena Engel, Alina Hartmann, Sandra Duquesne, Livius Penter, Geoffroy Andrieux, Lukas Rindlisbacher, Andrea Acerbis, Jule Ehmann, Christoph Köllerer, Michela Ansuinelli, Andres Rettig, Kevin Moschallski, Petya Apostolova, Tilman Brummer, Anna L Illert, Markus A Schramm, Yurong Cheng, Anna Köttgen, Justus Duyster, Hans D Menssen, Jerome Ritz, Bruce R Blazar, Melanie Boerries, Annette Schmitt-Gräff, Nurefsan Sariipek, Peter Van Galen, Joerg M Buescher, Nina Cabezas-Wallscheid, Heike L Pahl, Erika L Pearce, Robert J Soiffer, Catherine J Wu, Luca Vago, Burkhard Becher, Natalie Köhler, Tobias Wertheimer, Vijay K Kuchroo, Robert Zeiser

Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti–TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti–TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ Tc enhanced Tc activation, proliferation, and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and …

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Jun 2024 • Clinical hematology international 6 (2), 62, 2024

Single-cell genomics-based immune and disease monitoring in blood malignancies

Anja C Rathgeber, Leif S Ludwig, Livius Penter

Achieving long-term disease control using therapeutic immunomodulation is a long-standing concept with a strong tradition in blood malignancies. Besides allogeneic hematopoietic stem cell transplantation that continues to provide potentially curative treatment for otherwise challenging diagnoses, recent years have seen impressive progress in immunotherapies for leukemias and lymphomas with immune checkpoint blockade, bispecific monoclonal antibodies, and CAR T cell therapies. Despite their success, non-response, relapse, and immune toxicities remain frequent, thus prioritizing the elucidation of the underlying mechanisms and identifying predictive biomarkers. The increasing availability of single-cell genomic tools now provides a system’s immunology view to resolve the molecular and cellular mechanisms of immunotherapies at unprecedented resolution. Here, we review recent studies that leverage …

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Jun 2024 • The Journal of Clinical Investigation

Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti–TIM-3 therapy in mice

Nana Talvard-Balland, Lukas M Braun, Karen O Dixon, Melissa Zwick, Helena Engel, Alina Hartmann, Sandra Duquesne, Livius Penter, Geoffroy Andrieux, Lukas Simon Rindlisbacher, Andrea Acerbis, Jule Ehmann, Christoph Köllerer, Michela Ansuinelli, Andres Rettig, Kevin Moschallski, Petya Apostolova, Tilman Brummer, Anna L Illert, Markus A Schramm, Yurong Cheng, Anna Köttgen, Justus Duyster, Hans D Menssen, Jerome Ritz, Bruce R Blazar, Melanie Boerries, Annette Schmitt Graeff, Nurefsan Sariipek, Peter van Galen, Joerg M Buescher, Nina Cabezas-Wallscheid, Heike L Pahl, Erika L Pearce, Robert J Soiffer, Catherine J Wu, Luca Vago, Burkhard Becher, Natalie Köhler, Tobias Wertheimer, Vijay K Kuchroo, Robert Zeiser

Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting TIM-3 for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab-treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment-resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ T cells (Tc) enhanced Tc activation, proliferation and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3-treatment …

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Jun 2024 • OSF, 2024

Orientation fields predict perception of 3D shape from shading

Celine Aubuchon, Romain Vergne, Steven A Cholewiak, Benjamin Kunsberg, Daniel Holtmann-Rice, Steven Zucker, Roland Fleming

How the brain recovers the 3D structure of surfaces and objects from 2D retinal images remains mysterious. Shading patterns provide one of the most powerful—yet least understood—visual depth cues. Most theories assume the brain infers surface normals from luminance values. However, this seems unlikely as visual neurons are broadly insensitive to luminance. To identify alternative cues, we measured responses of model orientation-selective cell populations to images of shaded objects. We found a surprising statistical relationship between image orientations and surface curvatures, suggesting a novel way to estimate shape from shading. We find that the orientation-based cues not only predict striking novel illusions of shape perception when lighting varies, but also the impressive robustness of shape perception when large image modifications are introduced to directly pit luminance and image orientation cues against one another. The findings resolve the longstanding question of which image measurements drive shape from shading perception.

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Jan 2024 • Nature Communications

Integrative genotyping of cancer and immune phenotypes by long-read sequencing

Livius Penter, Mehdi Borji, Adi Nagler, Haoxiang Lyu, Wesley S Lu, Nicoletta Cieri, Katie Maurer, Giacomo Oliveira, Aziz M Al’Khafaji, Kiran V Garimella, Shuqiang Li, Donna S Neuberg, Jerome Ritz, Robert J Soiffer, Jacqueline S Garcia, Kenneth J Livak, Catherine J Wu

Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural ‘barcodes’, we define the optimal targets for nanoranger, namely those loci close to the 5’ end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to …

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Jan 2024 • bioRxiv

A community challenge to predict clinical outcomes after immune checkpoint blockade in non-small cell lung cancer

Michael Mason, Oscar Lapuente-Santana, Anni S Halkola, Wenyu Wang, Raghvendra Mall, Xu Xiao, Jacob Kaufman, Jingxin Fu, Jacob Pfeil, Jineta Banerjee, Verena Chung, Han Chang, Scott D Chasalow, Hung Ying Lin, Rongrong Chai, Thomas Yu, Francesca Finotello, Tuomas Mirtti, Mikko I Mayranpaa, Jie Bao, Emmy W Verschuren, Eiman I Ahmed, Michele Ceccarelli, Lance D Miller, Gianni Monaco, Wouter RL Hendrickx, Shimaa Sherif, Lin Yang, Ming Tang, Shengqing Stan Gu, Wubing Zhang, Yi Zhang, Zexian Zeng, Avinash Das Sahu, Yang Liu, Wenxian Yang, Davide Bedognetti, Jing Tang, Federica Eduati, Teemu D Laajala, William J Geese, Justin Guinney, Joseph D Szustakowski, David P Carbone, Benjamin G Vincent

BackgroundPredictive biomarkers of immune checkpoint inhibitor (ICI) efficacy are currently lacking for non-small cell lung cancer (NSCLC). Here, we describe the results from the Anti–PD-1 Response Prediction DREAM Challenge, a crowdsourced initiative that enabled the assessment of predictive models by using data from two randomized controlled clinical trials (RCTs) of ICIs in first-line metastatic NSCLC.MethodsParticipants developed and trained models using public resources. These were evaluated with data from the CheckMate 026 trial (NCT02041533), according to the model-to-data paradigm to maintain patient confidentiality. The generalizability of the models with the best predictive performance was assessed using data from the CheckMate 227 trial (NCT02477826). Both trials were phase III RCTs with a chemotherapy control arm, which supported the differentiation between predictive and prognostic …

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2024 • bioRxiv

Artifacts in single-cell mitochondrial DNA mutation analyses misinform phylogenetic inference

Caleb A Lareau, Michael S Chapman, Livius Penter, Tal Nawy, Dana Pe'er, Leif S Ludwig

Sequencing mitochondrial DNA (mtDNA) variants from single cells has resolved clonality and lineage in native human samples and clinical specimens. Prior work established that heteroplasmic mtDNA variants can be used to delineate clonality in hematopoiesis, but they have limited ability to reconstruct cellular phylogenies. However, a recent report by Weng et al. challenges the current paradigm by describing an unprecedented number of shared mtDNA variants between cells that reportedly resolve high-resolution phylogenetic trees. We re-examined the claims of Weng et al., and identified two major points of concern regarding this unprecedented connectedness. First, shared variants between cells are disproportionately detected in a single molecule per cell, and second, these variants are enriched 10-20-fold at the edges of mtDNA molecules, reminiscent of artifacts reported in other sequencing approaches. Further, our analyses show that pruning low support and likely artificial mtDNA variants removes nearly all of the reported phylogenetic structure. Thus, we strongly caution against using mtDNA variant calling workflows that rely on minimal evidence, including the computational pipeline introduced in Weng et al., as variants with high connectedness and low evidence are likely artifacts that lead to the construction of false phylogenies.

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2024 • bioRxiv

STHD: probabilistic cell typing of single Spots in whole Transcriptome spatial data with High Definition

Chuhanwen Sun, Yi Zhang

Recent spatial transcriptomics (ST) technologies have enabled sub-single-cell resolution profiling of gene expression across the whole transcriptome. However, the transition to high-definition ST significantly increased sparsity and dimensionality, posing computational challenges in discerning cell identities, understanding neighborhood structure, and identifying differential expression - all are crucial steps to study normal and disease ST samples. Here we present STHD, a novel machine learning method for probabilistic cell typing of single spots in whole-transcriptome, high-resolution ST data. Unlike current binning-aggregation-deconvolution strategy, STHD directly models gene expression at single-spot level to infer cell type identities. It addresses sparsity by modeling count statistics, incorporating neighbor similarities, and leveraging reference single-cell RNA-seq data. We demonstrated that STHD accurately predicts cell type identities at single-spot level, which automatically achieved precise segmentation of global tissue architecture and local multicellular neighborhoods. The STHD labels facilitated various downstream analyses, including cell type-stratified bin aggregation, spatial compositional comparison, and cell type-specific differential expression analyses. These high-resolution labels further defined frontlines of inter-cell type interactions, revealing direct cell-cell communication activities at immune hubs of a colon cancer sample. Overall, computational modeling of high-resolution spots with STHD uncovers precise spatial organization and deeper biological insights for disease mechanisms.

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2024 • Clinical hematology international 6 (2), 62, 2024

Single-cell genomics-based immune and disease monitoring in blood malignancies

Anja C Rathgeber, Leif S Ludwig, Livius Penter

Achieving long-term disease control using therapeutic immunomodulation is a long-standing concept with a strong tradition in blood malignancies. Besides allogeneic hematopoietic stem cell transplantation that continues to provide potentially curative treatment for otherwise challenging diagnoses, recent years have seen impressive progress in immunotherapies for leukemias and lymphomas with immune checkpoint blockade, bispecific monoclonal antibodies, and CAR T cell therapies. Despite their success, non-response, relapse, and immune toxicities remain frequent, thus prioritizing the elucidation of the underlying mechanisms and identifying predictive biomarkers. The increasing availability of single-cell genomic tools now provides a system’s immunology view to resolve the molecular and cellular mechanisms of immunotherapies at unprecedented resolution. Here, we review recent studies that leverage …

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2024 • medRxiv

Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence

Aude Chapuis, Francesco Mazziotta, Lauren Martin, Daniel N Eagan, Merav Bar, Sinead Kinsella, Kelly G Paulson, Valentin Voillet, Miranda C Lahman, Daniel Hunter, Thomas M Schmitt, Natalie Duerkopp, Cecilia CS Yeung, Tzu-Hao Tang, Raphael Gottardo, Yuta Asano, Elise C Wilcox, Bo Lee, Tianzi Zhang, Paolo Lopedote, Livius Penter, Catherine J Wu, Filippo Milano, Philip D Greenberg

Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+ T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (TTCR-C4). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 did not clearly improve outcomes in fifteen patients with active disease post-HCT. TCRC4-transduced EBV-specific T cells persisted longer post-transfer than CMV-specific T cells. Persisting TTCR-C4 skewed towards dysfunctional natural killer-like terminal differentiation, distinct from the dominant exhaustion programs reported for T-cell therapies targeting solid tumors. In one patient with active AML post-HCT, a sustained TTCR-C4 effector-memory profile correlated with long-term TTCR-C4 persistence and disease control. These findings reveal complex mechanisms underlying AML-induced T-cell dysfunction, informing future therapeutic strategies for addressing post-HCT relapse.

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Dec 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, Sebastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M Parry, Julien Broseus, Romain Guieze, Fabienne Lucas, Maria Hernandez-Sanchez, 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’s syndrome [RS]). Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed co-selection 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, down-modulation of the receptor …

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Dec 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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Nov 2023 • Blood

Ipilimumab plus decitabine for patients with MDS or AML in posttransplant 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


Nov 2023 • Blood

An Analytic Framework for the Prediction of Gvl Minor Histocompatibility Antigens to Prevent or Treat Post-Transplant Relapse

Nicoletta Cieri, Liang Li, Nidhi Hookeri, Kari Stromhaug, Julia Keating, Jonathan Stevens, Kameron Kooshesh, Helen Ji, Gabrielle M Hernandez, Jennifer Abelin, Susan Klaeger, Cleo Forman, Karl Clauser, Siranush Sarkizova, Giacomo Oliveira, Livius Penter, Haesook T Kim, William Lane, Shuqiang Li, Kenneth J Livak, Steven A Carr, Derin B Keskin, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Donna S Neuberg, Chip Stewart, Gad Getz, Catherine J Wu

The therapeutic effect of allo-HSCT relies on T cell alloreactivity driven by genetic nonidentity between donor and recipient (D-R) pairs. In the setting of HLA-matched transplants, endogenous proteins in recipient cells differing from those of the donor due to genetic polymorphisms, can provide distinct HLA-binding peptides, serving as minor histocompatibility antigens (mHAgs). Hematopoietically-restricted mHAgs represent ideal targets to separate graft-versus-leukemia (GvL) from graft-versus-host-disease (GvHD) effects. To date,however, the quest for optimal GvL mHAgs has resulted in the identification of only a handful of targets, raising concerns on the clinical feasibility of their targeting.We hypothesized that systematic mHAg prediction from whole-exome sequencing (WES) of D-R pairs could help identifying novel candidate mHAgs with an acceptable safety profile for therapeutical targeting. We focused on …

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Nov 2023 • Blood

Coordinated immune cell networks in the bone marrow microenvironment define the graft versus leukemia response with adoptive cellular therapy

Alexandria Maurer, Cameron Y Park, Shouvik Mani, Mehdi Borji, Crystal Shin, Livius Penter, James R Brenner, Jackson Southard, Wesley S Lu, Haoxiang Lyu, Shuqiang Li, Kenneth J Livak, Jerome Ritz, Robert J Soiffer, Elham Azizi, Catherine J Wu

Donor lymphocyte infusion (DLI) is an established therapy for relapsed acute myeloid leukemia (AML) after hematopoietic stem cell transplant (HSCT), but response rates are poor (~20%). Interactions between leukemia and immune cells within the leukemia microenvironment may determine responsiveness to adoptive cellular immunotherapies. We hypothesized that systematic characterization of the leukemic marrow microenvironment over treatment course with DLI would define leukemia-immune cell interactions critical to response and hence provide mechanistic understanding of the graft-versus-leukemia (GvL) effect. In particular, we anticipated that use of multi-modal single-cell sequencing across patients and time points before and after therapy accounting for temporal dependencies would facilitate disentangling of the complex microenvironment of leukemic marrow.To infer cell-cell interactions in a …

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Nov 2023 • Blood

An Analytic Framework for the Prediction of Gvl Minor Histocompatibility Antigens to Prevent or Treat Post-Transplant Relapse

Nicoletta Cieri, Liang Li, Nidhi Hookeri, Kari Stromhaug, Julia Keating, Jonathan Stevens, Kameron Kooshesh, Helen Ji, Gabrielle M Hernandez, Jennifer Abelin, Susan Klaeger, Cleo Forman, Karl Clauser, Siranush Sarkizova, Giacomo Oliveira, Livius Penter, Haesook T Kim, William Lane, Shuqiang Li, Kenneth J Livak, Steven A Carr, Derin B Keskin, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Donna S Neuberg, Chip Stewart, Gad Getz, Catherine J Wu

The therapeutic effect of allo-HSCT relies on T cell alloreactivity driven by genetic nonidentity between donor and recipient (D-R) pairs. In the setting of HLA-matched transplants, endogenous proteins in recipient cells differing from those of the donor due to genetic polymorphisms, can provide distinct HLA-binding peptides, serving as minor histocompatibility antigens (mHAgs). Hematopoietically-restricted mHAgs represent ideal targets to separate graft-versus-leukemia (GvL) from graft-versus-host-disease (GvHD) effects. To date,however, the quest for optimal GvL mHAgs has resulted in the identification of only a handful of targets, raising concerns on the clinical feasibility of their targeting.We hypothesized that systematic mHAg prediction from whole-exome sequencing (WES) of D-R pairs could help identifying novel candidate mHAgs with an acceptable safety profile for therapeutical targeting. We focused on …

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Nov 2023 • Blood

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy

Alexandria Maurer, Cameron Y Park, Shouvik Mani, Mehdi Borji, Crystal Shin, Livius Penter, James R Brenner, Jackson Southard, Wesley S Lu, Haoxiang Lyu, Shuqiang Li, Kenneth J Livak, Jerome Ritz, Robert J Soiffer, Elham Azizi, Catherine J Wu

Donor lymphocyte infusion (DLI) is an established therapy for relapsed acute myeloid leukemia (AML) after hematopoietic stem cell transplant (HSCT), but response rates are poor (~20%). Interactions between leukemia and immune cells within the leukemia microenvironment may determine responsiveness to adoptive cellular immunotherapies. We hypothesized that systematic characterization of the leukemic marrow microenvironment over treatment course with DLI would define leukemia-immune cell interactions critical to response and hence provide mechanistic understanding of the graft-versus-leukemia (GvL) effect. In particular, we anticipated that use of multi-modal single-cell sequencing across patients and time points before and after therapy accounting for temporal dependencies would facilitate disentangling of the complex microenvironment of leukemic marrow.To infer cell-cell interactions in a …

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Nov 2023 • Blood

Integrative Single-Cell Tracking of Clonal Evolution, Leukemia Phenotypes and Donor Engraftment Following Allogeneic Stem Cell Transplant Using Mitochondrial DNA Mutations

Livius Penter, Nicoletta Cieri, Katie Maurer, Haoxiang Lyu, Wesley S Lu, Giacomo Oliveira, Satyen H Gohil, Caleb Lareau, Leif S Ludwig, Shuqiang Li, Jerome Ritz, Jacqueline S Garcia, Robert J Soiffer, Kenneth J Livak, Catherine J Wu

Mitochondrial DNA (mtDNA) mutations can distinguish cells from unrelated individuals and their spectrum per patient sample can evolve following therapeutic bottlenecks. As such, these natural barcodes can potentially enable integrated single cell tracking of chimeric cellular populations and clonal evolution following unrelated allogeneic hematopoietic stem cell transplantation (HSCT). However, the feasibility of mtDNA-based donor-recipient deconvolution or identification of leukemia-specific phenotypes and the extent of co-evolution with somatic mutations remains unknown. If confirmed, post-transplant monitoring using mtDNA mutations could enable detection of early post-HSCT relapse and provide qualitative information on leukemia phenotypes, clonal evolution, or residual donor engraftment via a combined single cell assay.To investigate the extent of co-evolution of somatic nuclear mutations with mtDNA …

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Nov 2023 • Blood

Systematic Prediction of Minor Histocompatibility Antigens to Inform GvHD Outcomes after Allogeneic Stem Cell Transplantation

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Liang Li, Julia Keating, Jonathan Stevens, Kameron Kooshesh, Helen Ji, Gabrielle M Hernandez, Jennifer Abelin, Susan Klaeger, Cleo Forman, Karl Clauser, Siranush Sarkizova, Giacomo Oliveira, Livius Penter, Haesook T Kim, William Lane, Shuqiang Li, Kenneth J Livak, Steven A Carr, Derin B Keskin, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Donna S Neuberg, Chip Stewart, Gad Getz, Catherine J Wu

T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms (SNPs, indels, frameshifts), is at the core of the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the crucial role of mHAgs in graft-versus-leukemia and graft-versus-host (GvHD) reactions, it has not been possible thus far to consistently link patient-specific mHAg repertoires to clinical outcomes. As a result, only D-R HLA matching and the activity of GvHD prophylaxis strategies are currently available to help clinicians in this challenge.We hypothesized that post-transplant outcomes could be impacted by genome-wide mHAg load, delineated in an organ- and malignancy-specific fashion. We have therefore devised an analytic framework to systematically identify autosomal and Y-encoded mHAgs, based …

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Nov 2023 • BLOOD 142, 2023

Cellular Immunotherapies: Early Phase and Investigational TherapiesLeukemia Blasts Induce NK-like Dysfunction in AML-Specific T Cells

Francesco Mazziotta, Lauren E Martin, Miranda Lahman, Daniel N Egan, Sinead Kinsella, Kelly Paulson, Yapeng Su, Valentin Voillet, Livius Penter, Catherine J Wu, Philip Greenberg, Aude G Chapuis


Nov 2023 • Blood

Systematic Prediction of Minor Histocompatibility Antigens to Inform GvHD Outcomes after Allogeneic Stem Cell Transplantation

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Liang Li, Julia Keating, Jonathan Stevens, Kameron Kooshesh, Helen Ji, Gabrielle M Hernandez, Jennifer Abelin, Susan Klaeger, Cleo Forman, Karl Clauser, Siranush Sarkizova, Giacomo Oliveira, Livius Penter, Haesook T Kim, William Lane, Shuqiang Li, Kenneth J Livak, Steven A Carr, Derin B Keskin, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Donna S Neuberg, Chip Stewart, Gad Getz, Catherine J Wu

T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms (SNPs, indels, frameshifts), is at the core of the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the crucial role of mHAgs in graft-versus-leukemia and graft-versus-host (GvHD) reactions, it has not been possible thus far to consistently link patient-specific mHAg repertoires to clinical outcomes. As a result, only D-R HLA matching and the activity of GvHD prophylaxis strategies are currently available to help clinicians in this challenge.We hypothesized that post-transplant outcomes could be impacted by genome-wide mHAg load, delineated in an organ- and malignancy-specific fashion. We have therefore devised an analytic framework to systematically identify autosomal and Y-encoded mHAgs, based …

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