About

Dr. Martina Damo is a faculty member at The University of Chicago, where her lab is part of the Section of Rheumatology within the Department of Medicine. Her research investigates how immune cells, specifically T cells, are regulated in healthy tissues to maintain immunological tolerance and in cancer to promote anti-cancer immunity. She also studies the consequences of cancer immunotherapy on T cells in both cancerous and healthy tissues. Dr. Damo's lab is composed of young scientists passionate about understanding the physiology of immune regulation with the goal of improving the efficacy and safety of immunotherapy. She is a member of the Committees on Immunology, Cancer Biology, and Molecular Metabolism and Nutrition, and is also affiliated with the UChicago Comprehensive Cancer Center.

Research topics

• Immunology
• Biology
• Cell biology
• Cancer research
• Genetics
• Pathology
• Medicine

Selected publications

• KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

  Science · 2025-02-13 · 65 citations

  articleOpen access

  Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

  PublisherOA PDFDOI

• CD8 T cells mediate immunosurveillance for neoantigen+ epithelial stem cells in the colon

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-19 · 1 citations

  preprint

  Summary Epithelial cells in the colon accumulate substantial numbers of somatic mutations, some of which can be recognised as neoantigens. The ability of CD8 T cells to survey for neoantigen+ cells in the healthy colon would provide an early detection mechanism to prevent cancer, but it is unclear whether neoantigen-specific CD8 T cells can mediate this process of immunosurveillance without becoming tolerant. To address this question, we used a genetically engineered mouse model to express a neoantigen in the epithelial cells of the adult proximal colon. Induction of neoantigen expression led to rapid elimination of neoantigen+ epithelial cells from the colon in a CD8 T cell-dependent manner. Neoantigen-specific CD8 T cells acquired cytolytic function within the colon tissue under steady-state conditions, which was required for elimination of the neoantigen+ epithelial cells. Despite the elimination of ∼25% of their epithelial cells over a two-day period, the colons looked histologically normal. Immunofluorescence and single-cell transcriptomic analyses revealed that neoantigen-specific CD8+ T cells specifically target neoantigen+ stem cells at the crypt base, which was associated with Ki67 in the crypt wall and abundance of neoantigen-negative stem cells. Infiltrating neoantigen-specific CD8 T cells made IFNg and expressed PD-1, raising the question of why PD-1-dependent suppression did not prevent the acquisition of effector functions by these neoantigen-specific CD8 T cells. Despite an increased signature of interferon-stimulated genes in colonic epithelial cells, PD-L1 expression was surprisingly absent. Moreover, we found that colonic epithelial stem cells also did not express PD-L1 under conditions of chronic inflammation, such as ulcerative colitis, immune checkpoint-induced colitis, and ageing, or when directly stimulated with IFN-γ in vitro . Analyses of the PD-L1 gene promoter across humans and mice showed hypermethylation at sites associated with PD-L1 repression in cancer. Thus, our data support a model in which the acquisition of neoantigens by colonic epithelial cells triggers CD8 T cell-mediated immunosurveillance. This results in the elimination of PD-L1-negative neoantigen+ stem cells by effector CD8 T cells and simultaneous repair of the colon by neoantigen-negative epithelial cells to prevent immunopathology.

  PublisherDOI

• Intestinal tuft cell immune privilege enables norovirus persistence

  Science Immunology · 2024-03-22 · 19 citations

  articleOpen access

  The persistent murine norovirus strain MNV CR6 is a model for human norovirus and enteric viral persistence. MNV CR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV CR6 induces functional MNV-specific CD8 + T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8 + T cells by adoptively transferring JEDI (just EGFP death inducing) CD8 + T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8 + T cell–mediated killing—unlike Lgr5 + intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8 + T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8 + T cells neither cleared nor prevented MNV CR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8 + T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.

  PublisherOA PDFDOI

• PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens

  Nature · 2023-06-21 · 73 citations

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Mapping the gene space at single-cell resolution with gene signal pattern analysis

  The Journal of Immunology · 2023-05-01

  articleOpen access

  Abstract In single-cell RNA sequencing analysis, several computational methods have been developed to map the cellular state space, but little has been done to map the gene space. A mapping that preserves gene-gene relationships within the dataset is particularly useful for characterizing cellular heterogeneity within cell types, where boundaries between cell subpopulations are often unclear or even arbitrary. Here, we present gene signal pattern analysis, a new paradigm for analyzing single cells. We build a cell-cell graph and design a dictionary of diffusion wavelets, capturing a multiscale view of the cell space. We then transform genes by the dictionary and learn a reduced gene representation. Given the gap in prior research for this problem, we design nine alternative strategies and three benchmarks for evaluating preservation of gene-gene relationships, all of which are outperformed by diffusion wavelet-transformed signals. We also define, calculate, and evaluate localization, a key property of a gene signal on the cellular graph. We demonstrate the utility of gene signal pattern analysis on T cells from a mouse model of peripheral tolerance in skin. The gene space mapping reveals a continuum of gene signals characterized by T cell subtypes and transcriptional programs related to effector function and proliferation. Furthermore, we built a multiscale manifold of 48 melanoma patient samples, demonstrating the ability of our method to characterize differences between responders and non-responders to checkpoint immunotherapy. Together, we show gene signal pattern analysis, through methodology from graph signal processing, spectral graph theory, and machine learning, represents an avenue for future research in scRNA-seq analysis. Gruber Foundation

  PublisherOA PDFDOI

• Tuft cell tropism enables norovirus evasion of CD8+ T cells and viral persistence

  The Journal of Immunology · 2023-05-01

  articleOpen access

  Abstract Human norovirus (HNV) is a leading cause of viral gastroenteritis. Infection fails to elicit durable immunity and can cause chronic asymptomatic shedding. It is not known how norovirus escapes the adaptive immune response, and rigorous studies of the host and viral determinants underlying immune evasion are impeded by the lack of scalable cell culture systems and reverse genetic tools. Murine norovirus (MNV) recapitulates many aspects of HNV and enables studying norovirus biology in vitro and in vivo. MNVCW3 causes non-persistent infection with long-lasting immune memory, whereas MNVCR6 causes persistent infection despite inducing functional MNV-specific CD8+ T cells. We recently identified that MNVCR6 and other persistent MNV strains require tuft cells for chronic enteric infection. Tuft cells are rare, chemosensory epithelial cells with roles in pathogen surveillance, epithelial repair, and tumorigenesis. To interrogate tuft cell interactions with CD8+ T cells, we adoptively transferred JEDI (Just EGFP Death Inducing) CD8+ T cells that detect EGFP200–208 presented on H2-Kd into tuft cell reporter mice (Gfi1b-GFP). Surprisingly, tuft cells at steady state can resist JEDI CD8+ T cell-mediated killing despite normal levels of surface MHC-I. In contrast, Lgr5+ intestinal stem cells and extraintestinal tuft cells are highly susceptible to clearance by JEDI CD8+ T cells. We further find that JEDI CD8+ T cells cannot clear nor prevent MNVCR6 infection of tuft cells, suggesting that tuft cells offer a replicative niche for immune escape and viral persistence. Whether HNV infects tuft cells during chronic asymptomatic infection and whether tuft cell-derived cancers can evade CD8+ T cells will warrant further exploration in the future. Supported by grants from the NIH (K08 A1128043, R01 AI148467) and the NSF (DGE1752134)

  PublisherOA PDFDOI

• Novel Mouse Models for Cancer Immunology

  Annual Review of Cancer Biology · 2022-01-18 · 29 citations

  articleOpen access

  Mouse models for the study of cancer immunology provide excellent systems in which to test biological mechanisms of the immune response against cancer. Historically, these models have been designed to have different strengths based on the current major research questions at the time. As such, many mouse models of immunology used today were not originally developed to study questions currently plaguing the relatively new field of cancer immunology, but instead have been adapted for such purposes. In this review, we discuss various mouse model of cancer immunology in a historical context as a means to provide a fuller perspective of each model's strengths. From this outlook, we discuss the current state of the art and strategies for tackling future modeling challenges.

  PublisherOA PDFDOI

• 948 Developing engineered animal models to investigate tumor-specific T cell responses and immune-related adverse events after immunotherapy

  Regular and Young Investigator Award Abstracts · 2022-11-01

  articleOpen access1st authorCorresponding

  <h3>Background</h3> The rise of immune checkpoint blocking therapies (ICBs) as treatments across multiple cancer types has revealed a previously underappreciated role for the immune response in the natural regulation of cancer development. ICBs potentiate the functions of anti-tumor CD8 T cells, leading to durable tumor regression, yet, ICB treatment (particularly combination ICB) is associated with frequent and poorly-understood immune related adverse events (irAEs), which has limited the broader use of combination ICB. Thus, it is important to better understand how ICBs impact T cell responses in both tumor and non-tumor contexts, and these differ. <h3>Methods</h3> A major gap in the field remains the availablity of animal models that faithfully recapitulate the immune-tumor microenvironment associated with different types of human cancers, and models that recapitulate the disease biology of irAEs. Our laboratory previously developed the iNversion INducible Joined neoAntigen (NINJA) model, which allows for tight spatial and temporal regulation of the induction of an known neoantigen. Using NINJA, my lab has now developed autochthonous genetically engineered mouse cancer models for studying anti-tumor T cell responses and models for studying the mechanisms by which ICBs break peripheral T cell tolerance and result in irAEs. We use paired single cell-RNAseq (scRNAseq) and T cell receptor (TCR) seq to validate that our NINJA models faithfully recapitulate the responses of T cells participating in human irAEs and in human cancer. Moreover, because T cells recognize the same antigen across all our models, tumor-specific and disease-causing CD8 and CD4 T cells can be directly compared. <h3>Results</h3> In a model of skin-antigen induction, we identified recruitment of CD11c+ CD11b+ CD14+ CD16+ PD-L1+ myeloid cells in response to effector CD8 T cell infiltration, but not disease—unless mice are also treated with anti-PD-1 antibodies—suggesting that skin myeloid cells prevent disease pathology via the PD-1 pathway. Analyses of the CD8 T cells showed a PD-1-blockade induced upregulation of CD103 and Granzyme A, but otherwise minimal transcriptional impact. By contrast, protein-level increases in effector cytokines and degranulation were associated with blockade, as was migration into the epidermis and tissue destruction. Similar clonal CD8 T cell expansion and increased effector gene expression was seen in skin irAE patients. <h3>Conclusions</h3> These data highlight that NINJA serves as platform for understanding mechanisms that lead to irAEs in different tissues, which could be used to testing interventions to prevent ICB-induced disease. Ongoing work focuses on elucidating the role of PD-1/PD-L1 in skin-myeloid cell-mediated suppression of skin-specific CD8 T cells.

  PublisherOA PDFDOI

• Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection

  The Journal of Experimental Medicine · 2022 · 83 citations

  • Biology
  • Cell biology
  • Immunology

  Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells. Trajectory analyses and infection models showed intermediate cells arise from progenitor cells before bifurcating into terminal effector and exhausted subsets. Genetic ablation experiments identified that type I IFN drives exhaustion through an IRF7-dependent mechanism, possibly through an IFN-stimulated subset bridging progenitor and exhausted cells. Conversely, Zeb2 was critical for generating effector cells. Intriguingly, some T cell clones exhibited lineage bias. Mechanistically, we identified that TCR avidity correlates with an exhausted fate, whereas SHP-1 selectively restricts low-avidity effector cell accumulation. Thus, our work elucidates novel mechanisms underlying CD8+ T cell fate determination during persistent infection and suggests two potential pathways leading to exhaustion.

  PublisherOA PDFDOI

• LB778 A quantitative scoring system for cutaneous immune-related adverse events

  Journal of Investigative Dermatology · 2021-08-19

  article
  PublisherDOI

Frequent coauthors

• Nikhil S. Joshi

  Yale University

  21 shared

• Jeffrey A. Hubbell

  University of Chicago

  17 shared

• David S. Wilson

  14 shared

• Thierry VandenDriessche

  KU Leuven

  14 shared

• Luigi Naldini

  Vita-Salute San Raffaele University

  13 shared

• Can Cui

  Henan University

  11 shared

• Kelli A. Connolly

  Yale University

  9 shared

• Ivana William

  Yale University

  8 shared

Labs

• Damo LabPI