publications

2024

1. 

   Naturally occurring T cell mutations enhance engineered T cell therapies

   Julie Garcia^*, Jay Daniels^*, Yujin Lee, Iowis Zhu, Kathleen Cheng, Qing Liu, Daniel Goodman, Cassandra Burnett, Calvin Law, Chloë Thienpont, Josef Alavi, Camillia Azimi, Garrett Montgomery, Kole T. Roybal, and Jaehyuk Choi

   Nature, 2024

   *Co-first authors
   Covered in: Nature Podcast | Nature Biotechnology | Nature Immunology | Cancer Discovery | National Cancer Institute | Fierce Biotech

   abstract PDF

   Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11–PIK3R3, found in a CD4+ cutaneous T cell lymphoma, that augments CARD11–BCL10–MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11–PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.

2023

1. 

   PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma

   Tim Wartewig^*, Jay Daniels^*, Miriam Schulz^*, Erik Hameister, Abhinav Joshi, Joonhee Park, Emma Morrish, Anuroop V. Venkatasubramani, Filippo M. Cernilogar, Frits H. A. Heijster, Christian Hundshammer, Heike Schneider, Filippos Konstantinidis, Judith V. Gabler, Christine Klement, Henry Kurniawan, Calvin Law, Yujin Lee, Sara Choi, Joan Guitart, Ignasi Forne, Jérôme Giustinani, Markus Müschen, Salvia Jain, David M. Weinstock, Roland Rad, Nicolas Ortonne, Franz Schilling, Gunnar Schotta, Axel Imhof, Dirk Brenner, Jaehyuk Choi, and Jürgen Ruland

   Nature Cancer, 2023

   *Co-first authors
   Covered in: Nature Immunology

   abstract PDF

   The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.

2021

1. 

   BACH2 is a putative T-cell lymphoma tumor suppressor that may play a role in product-derived CAR T-cell lymphomas

   Jay Daniels and Jaehyuk Choi

   Blood, 2021

   PDF

2. 

   Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity

   Joonhee Park^*, Jay Daniels^*, Tim Wartewig^*, Kimberly G. Ringbloom, Maria Estela Martinez-Escala, Sara Choi, Jane J. Thomas, Peter G. Doukas, Jingyi Yang, Caroline Snowden, Calvin Law, Yujin Lee, Katie Lee, Yancong Zhang, Carly Conran, Kyle Tegtmeyer, Samuel H. Mo, David R. Pease, Balaji Jothishankar, Pui-Yan Kwok, Farah R. Abdulla, Barbara Pro, Abner Louissaint, Titus J. Boggon, Jeffrey Sosman, Joan Guitart, Deepak Rao, Jürgen Ruland, and Jaehyuk Choi

   Blood, 2021

   *Co-first authors

   abstract PDF

   Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor–dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes.

2020

1. 

   Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas

   Jay Daniels^*, Peter G. Doukas^*, Maria E. Martinez Escala, Kimberly G. Ringbloom, David J. H. Shih, Jingyi Yang, Kyle Tegtmeyer, Joonhee Park, Jane J. Thomas, Mehmet E. Selli, Can Altunbulakli, Ragul Gowthaman, Samuel H. Mo, Balaji Jothishankar, David R. Pease, Barbara Pro, Farah R. Abdulla, Christopher Shea, Nidhi Sahni, Alejandro A. Gru, Brian G. Pierce, Abner Louissaint, Joan Guitart, and Jaehyuk Choi

   Nature Communications, 2020

   *Co-first authors

   abstract PDF

   Primary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.

2022

1. The Robust Tumoricidal Effects of Combined BET/HDAC Inhibition in Cutaneous T-Cell Lymphoma Can Be Reproduced by \DeltaNp73 Depletion

   Lei Zhao, Tony Hsiao, Connor Stonesifer, Jay Daniels, Tiffany J Garcia-Saleem, Jaehyuk Choi, Larisa Geskin, Alain H Rook, and Gary S Wood

   Journal of Investigative Dermatology, 2022
2. Epigenetic regulation of apoptosis in cutaneous T-cell lymphoma: implications for therapy with methotrexate, JAK inhibitors, and resveratrol

   Minakshi Nihal, Jianqiang Wu, Connor J Stonesifer, Jay Daniels, Jaehyuk Choi, Larisa Geskin, Alain H Rook, and Gary S Wood

   Journal of Investigative Dermatology, 2022

2020

1. An Atypical Presentation of Propionibacterium Acnes Endophthalmitis Following Cataract Surgery

   Itamar Livnat, Jay Daniels, Leanne T Labriola, and Michael S Tsipursky

   Journal of VitreoRetinal Diseases, 2020

2017

1. Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p. Q575E)

   Joonhee Park, Jingyi Yang, Alexander T. Wenzel, Akshaya Ramachandran, Wung J. Lee, Jay C. Daniels, Juhyun Kim, Estela Martinez-Escala, Nduka Amankulor, Barbara Pro, Joan Guitart, Marc L. Mendillo, Jeffrey N. Savas, Titus J. Boggon, and Jaehyuk Choi

   Blood, 2017
2. Branch-specific plasticity of a bifunctional dopamine circuit encodes protein hunger

   Qili Liu, Masashi Tabuchi, Sha Liu, Lay Kodama, Wakako Horiuchi, Jay Daniels, Lucinda Chiu, Daniel Baldoni, and Mark N Wu

   Science, 2017