About

Professor Judy Lieberman leads the Lieberman Lab, which focuses on the study of cytotoxic T lymphocytes (CTL), crucial cells in immune defense against viral infections and cancer. The lab investigates how CTLs recognize infected or transformed cells and release cytolytic granules containing serine proteases called granzymes that induce programmed cell death or apoptosis. A significant area of research in the lab is the molecular pathways activated by granzymes, particularly Granzyme A, the most abundant CTL protease. Granzyme A induces a novel form of apoptosis independent of the caspase pathway, causing single strand nicks of DNA. The lab has identified new mechanisms of mitochondrial and DNA damage activated by Granzyme A. Additionally, the lab studies the regulation of cytotoxic T lymphocyte function, especially in chronic infections. Another major research focus of the Lieberman Lab is RNA interference (RNAi) and its role in normal cell differentiation and cancer. The lab aims to understand how RNAi can be harnessed to develop drugs for treating or preventing viral infections and cancer. Notably, the group was the first to demonstrate that RNAi could serve as a basis for therapy in an animal model. The lab also actively develops methods for targeting small RNAs into specific cell types in vivo. The Lieberman Lab is part of the Program in Cellular and Molecular Medicine at Boston Children's Hospital and is affiliated with the Harvard Medical School Immunology Program, Harvard Genetics Program, and Harvard Stem Cell Institute.

Research topics

• Immunology
• Biology
• Chemistry
• Medicine
• Virology
• Biochemistry
• Pharmacology
• Genetics
• Pathology
• Cell biology
• Cancer research
• Neuroscience
• Molecular biology

Selected publications

• Abstract LB082: Disrupting mismatch repair makes mismatch repair-proficient tumors immunogenic and induces CD8 T cell-dependent, but T cell receptor-independent, immune control of heterologous tumors in mice

  Cancer Research · 2026-04-17

  articleSenior author

  Abstract Mismatch repair-deficient (MMRd) tumors respond well to immune checkpoint blockade (ICB) while MMR-proficient (MMRp) tumors from the same cell type do not. We hypothesized that disrupting MMR would make immunologically cold MMRp tumors more immunogenic and responsive to ICB. Initial attempts to knockout individual MMR genes had a significant but weak impact on growth of implanted tumors because the development of microsatellite instability (MSI) and chromosomal instability (CIN) was slow relative to tumor growth and progression. However, simultaneous knockout of two MMR genes, Mlh1 and Msh2, in multiple mouse cancer cell lines and organoids (colorectal (CRC), breast (TNBC), and melanoma) led to rapid CD8⁺ T cell-mediated tumor growth inhibition or even rejection of subcutaneous and orthotopic tumor implants. Tumors that were not rejected could be ablated by treatment with anti-PD1. Mlh1-/-Msh2-/- tumors proliferated like wild-type tumors in vitro. In vivo tumor control was immune-mediated and depended on CD8 T cells since it was abrogated in immunodeficient NSG mice or by depletion of CD8 T cells, but not CD4 T cells or NK cells. Delayed or concurrent challenge of mice that reject Mlh1-/-Msh2-/- tumors with MMRp tumors also led to their rejection, indicating that exposure to MMRd tumors induces immune reactivity and memory to the MMRp tumor. Surprisingly, mice that rejected Mlh1-/-Msh2-/- CRC or TNBC tumors were also protected against heterologous CRC or TNBC cancers and even against B16F10 implants, suggesting that exposure to MMRd tumors led to CD8 T cell immunity that was independent of tumor antigens. In fact, knockout of B2m in Mlh1-/-Msh2-/- CRC tumors, which eliminated MHC class I expression and antigen presentation to CD8 T cells, did not affect tumor rejection, suggesting that immune protection was not T cell receptor-mediated. scRNA-seq, qRT-PCR and flow cytometry revealed profound remodeling of the tumor immune microenvironment in Mlh1-/-Msh2-/- tumors, characterized by up-regulation of interferon response genes by the tumor, an expansion of cytotoxic CD8⁺ T cells that express NK activating receptors, reduction in infiltrating neutrophils and a shift in myeloid populations toward less immunosuppressive, but more phagocytic, myeloid cells. Antitumor immunity generated by exposure to Mlh1-/-Msh2-/- tumors was driven by NK activating receptor recognition by CD8⁺ T cells of NK ligands on tumor cells, since protection was abrogated by treating tumor-bearing mice with an antibody to an NK activating receptor. Although no small molecule inhibitors of MMR have been identified, in vivo tumor-targeted knockdown of Mlh1 and Msh2 using EpCAM-targeted aptamer-siRNAs suppressed tumor growth. Thus, disrupting MMR in MMRp cancer cells induces a novel, potent CD8 T cell protective immune response that is mediated by an NK activating receptor that recognizes the genotoxic stress of unrepaired DNA damage in the tumor, rather than by T cell receptor recognition of tumor antigens, that strongly protects mice from MMRp and even unrelated tumors. These results in mice suggest that therapeutic strategies that make MMRp tumors MMRd could be developed to treat immunologically cold tumors or sensitize them to ICB. Citation Format: Haiwei Zhang, Ayijiang Yisimayi, Bowen Gu, Yuting Wang, Wayne M. Yokoyama, Sytse J. Piersma, Eduard Batlle, Daniele V. Tauriello, Judy Lieberman. Disrupting mismatch repair makes mismatch repair-proficient tumors immunogenic and induces CD8 T cell-dependent, but T cell receptor-independent, immune control of heterologous tumors in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB082.

  PublisherDOI

• Abstract 3232: NOP16 is a histone mimetic that regulates histone H3K27 methylation and gene repression

  Cancer Research · 2026-04-03

  article

  Abstract Post-translational modifications of histone tails alter chromatin accessibility to regulate gene expression. Some viruses exploit the importance of histone modifications by expressing histone mimetic proteins that contain histone-like sequences to sequester complexes that recognize modified histones. Here we identify an evolutionarily conserved and ubiquitously expressed, endogenous mammalian protein Nucleolar protein 16 (NOP16) that functions as a H3K27 mimic. NOP16 binds to EED in the H3K27 trimethylation PRC2 complex and to the H3K27 demethylase JMJD3. NOP16 competitively inhibits the interaction between EED and H3K27me3 and causes EED to translocate from the nucleoplasm to the nucleolus, thereby negatively regulating H3K27me3 modification in the nucleoplasm. NOP16 is overexpressed and linked to poor prognosis in breast cancer. Depletion of NOP16 in breast cancer cell lines causes cell cycle arrest, decreases cell proliferation and selectively decreases expression of E2F target genes and of genes involved in cell cycle, growth and apoptosis. Conversely, ectopic NOP16 expression in triple negative breast cancer cell lines increases cell proliferation, cell migration and invasivity in vitro and tumor growth in vivo, while NOP16 knockout or knockdown has the opposite effect. Thus, NOP16 is a histone mimic that competes with Histone H3 for H3K27 methylation and demethylation. When it is overexpressed in cancer, it derepresses genes that promote cell cycle progression to augment breast cancer growth. Citation Format: Aamir Khan, Ken Takashima, Dian-Jang Lee, María Fernanda Trovero, Xing Wang, M. Hafiz Rothi, Ying Zhang, Zilan Li, Sarah Niesen, Julia Natale, Ernst Schmid, Joseph Al Haddad, Sabine Dietmann, Sumio Ohtsuki, Shannan Ho Sui, Hiroyuki Oshiumi, Judy Lieberman, Eric Lieberman Greer. NOP16 is a histone mimetic that regulates histone H3K27 methylation and gene repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3232.

  PublisherDOI

• SARS-CoV-2 mRNA vaccination sensitizes tumors to immune checkpoint blockade

  Vita · 2026-01-01

  articleOpen accessSenior author

  A recent paper in Nature shows that SARS-CoV-2 mRNA vaccination within 100 days of beginning immune checkpoint inhibitor immunotherapy improves survival of cancer patients by systemically inducing Type I interferons, suggesting that an off-the-shelf cancer vaccine that potently stimulates innate immunity may not need to be customized to contain tumor-associated antigens to be effective.

  PublisherOA PDFDOI

• New insights into the noncanonical inflammasome point to caspase-4 as a druggable target

  Nature reviews. Immunology · 2025-03-05 · 16 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts

  Proceedings of the National Academy of Sciences · 2025-03-17 · 8 citations

  articleOpen access

  Maternal–fetal immune tolerance guarantees a successful pregnancy throughout gestation. HLA-G, a nonclassical human leukocyte antigen (HLA) molecule exclusively expressed in extravillous trophoblasts (EVT), is a crucial factor in establishing maternal–fetal immune tolerance by interacting with inhibitory receptors on various maternal immune cells residing in the uterus. While trophoblast-specific cis-regulatory elements impacting HLA-G transcription have been described, the identity of trans-acting factors controlling HLA-G expression in EVT remains poorly understood. Utilizing a genome-wide CRISPR-Cas9 knockout screen, we find that the WNT signaling pathway negatively regulates HLA-G expression in EVT. In addition, we identified two trophoblast-specific transcription factors, TEAD1 and TEAD3, required for HLA-G transcription in EVT in a Yes-associated protein-independent manner. Altogether, we systematically elucidated essential genes and pathways underlying HLA-G expression in EVT, shedding light on the mechanisms of maternal–fetal tolerance and potentially providing insights into controlling HLA-G expression beyond EVT to protect allogeneic cells from immune rejection.

  PublisherOA PDFDOI

• ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

  Proceedings of the National Academy of Sciences · 2025-08-19 · 2 citations

  articleOpen accessCorresponding

  Toll-like receptor 4 (TLR4), a pattern-recognition receptor located on the plasma membrane, senses extracellular danger signals to initiate inflammatory immune responses. It is initially synthesized in the endoplasmic reticulum (ER), undergoes N-linked glycosylation, and is subsequently transported to the Golgi before ultimately reaching the plasma membrane. However, the mechanisms underlying the processing and maturation of TLR4 in the ER remain elusive. Through whole genome-wide CRISPR screening, CCDC134 was identified as a critical and essential factor for TLR4-dependent inflammatory response. Localization of CCDC134 in the ER lumen rather than its exosome-mediated secretion is required for its role in TLR4 signaling. Loss of CCDC134 results in the retention of TLR4 in the ER for subsequent ER-associated degradation, and thus blockade of TLR4 maturation and plasma membrane trafficking. Defects in TLR4 processing and maturation in the ER in CCDC134-depleted cells are caused by aberrant hyperglycosylation and destabilization of glycoprotein 96 (gp96), a key chaperone of TLR4. These results suggest that CCDC134 controls gp96 glycosylation to facilitate TLR4 maturation in the ER.

  PublisherDOI

• Inflammatory cell death and anti-tumor immunity

  2025-10-14

  articleSenior author

  Different types of regulated cell death, including ferroptosis, necroptosis, and pyroptosis, can elicit an immune response. In this webinar, our speakers will introduce the concept of inflammatory/immunogenic cell death and discuss its implications for cancer immunity and immunotherapy. The presentations will be followed by a panel discussion and Q A session. The webinar will be hosted by Nature Cancer and Nature Communications editors.

  PublisherDOI

• Identification of cross-stage, cross-species malaria CD8+ T cell antigens

  Research Square · 2025-05-30

  preprintOpen access
  PublisherOA PDFDOI

• Innate immunity in tumour immunoediting and immunosurveillance

  The EMBO Journal · 2025-11-28

  articleOpen accessSenior author

  Abstract The successes of cancer immunotherapy have inspired research aiming to increase the number of immune-responsive cancers. The first effective immunotherapeutic strategies—immune checkpoint blockade (ICB) and CAR T cells—were designed to overcome limitations in CD8 + T cell recognition and killing of tumor cells. However, most solid tumors still do not respond to these measures and new treatment approaches are needed. Tumors evolve many strategies to avoid immune control. One way to identify immunotherapy strategies is to study what distinguishes immunotherapy-responsive and -unresponsive tumors. Another way is to identify the differences in tumors that emerge after carcinogen exposure in immunocompetent versus immunodeficient hosts. Still another way is to identify changes in gene expression in emerging tumors that enable them to escape immunosurveillance (known as tumor immunoediting). Evolving tumors suppress antigen processing and presentation to avoid triggering tumor-specific T cells but also repress key innate immune genes that transmit danger signals to immune cells. In this perspective, we discuss the roles of innate immunity in anti-tumor responses and consider how innate immunity could be harnessed to make tumors more immune-responsive.

  PublisherOA PDFDOI

• Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity

  Nature · 2025-05-21 · 43 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• Decidual NK response to infection

  NIH · $4.2M · 2019–2024

• NIH Grant R01AI042519

  NIH · $2.9M · 2006

• NIH Grant K08CA001449

  NIH · $359k · 1995

• NIH Grant R01AI030926

  NIH · $470k · 1994

• NIH Grant P01AI054558

  NIH · $8.7M · 2010

Frequent coauthors

• Premlata Shankar

  Tirunelveli Medical College

  133 shared

• Hao Wu

  Harvard University

  94 shared

• Michael M. Lederman

  Case Western Reserve University

  79 shared

• Paul R. Skolnik

  73 shared

• Marty S. Springer

  Merck & Co., Inc., Rahway, NJ, USA (United States)

  72 shared

• Derek M. Dykxhoorn

  Dr. John T. Macdonald Foundation

  72 shared

• Xing Liu

  University of Science and Technology of China

  70 shared

• Douglas D. Richman

  University of California System

  66 shared