The Thomas lab studies CD8 tissue-resident memory (T_RM) heterogeneity in the human gastrointestinal tract and liver, with the goal of leveraging these studies to improve the diagnosis and treatment of diverse immune-mediated diseases affecting digestive organs.

Our primary areas of focus are inflammatory colitis and hepatitis that develop in patients treated with immune checkpoint inhibitor therapy for cancer (i.e. “checkpoint colitis” and “checkpoint hepatitis”). These organ specific immune-related adverse events (irAEs) present a significant burden to patients and their treatment with anti-inflammatory medications can impair anti-tumor immune responses, thus leading to worse patient outcomes. Our studies have shown that CD8 T_RM cells are likely major culprits in these inflammatory pathologies involving the gastrointestinal tract and liver. Thus, the study of irAEs is important for improving the clinical care of cancer patients while providing a window into how CD8 T_RM cells and immune checkpoint pathways contribute to immune tolerance in the healthy gastrointestinal tract and liver. While our studies primarily focus on immune checkpoint inhibitor toxicities, we also seek to extend our findings towards a better understanding of spontaneous autoimmune diseases such as microscopic colitis, autoimmune hepatitis, Crohn’s disease, and Ulcerative Colitis.

We use a wide variety of tools for our studies including multi-spectral flow cytometry and microscopy, traditional cellular immunology assays on primary immune populations and cell lines, and “multi-omic” approaches including bulk and single-cell sequencing, single-cell antigen receptor sequencing, and proteomic studies.

Defining epigenetic landscape and effector functions of human CD8 tissue-resident memory T cells in human gastrointestinal tract

Seminal work in tumor immunology has shown that immune checkpoint inhibitor (ICI) therapy functions primarily by reinvigoration chronically antigen stimulated CD8 T cells that have become functionally exhausted. Exhausted CD8 T cells have impaired effector functions and an altered epigenetic landscape that is as different from that of conventional T cells as conventional T cells are from other immune lineages like B cells and macrophages. While exhausted T cells show impaired tumor clearance, they may play an important role in limiting immune responses in epithelial barrier tissues that are in constant contact with diverse antigenic environments. Thus, T cell exhaustion may represent an important mechanism for preventing autoimmune responses in the healthy gut, though if these exhausted transcriptional programs exist in subsets of resident T cells in the human intestine and how they are regulated is not understood. We are investigating if the tissue CD8 T_RM subtypes that become activated in checkpoint colitis patients share epigenetic and effector features of exhausted cells using in vitro cellular assays and querying the epigenetic landscapes of this heterogeneous CD8 T cell population with genome-wide, single-cell assays to analyze regions of open chromatin in these cell types.

Defining the spatial distribution of immune subsets in inflammatory colitis

Our prior work showed that in patients with checkpoint inhibitor colitis, there is marked upregulation of interferon stimulated genes with important functions in immune homing, antigen presentation, T cell activation, and epithelial absorptive capacity. This interferon signature was strongest at the luminal side of the intestinal mucosa, suggesting that inflammatory immune responses in colitis likely vary along the crypt axis. We hypothesize that in irColitis, CD8 T_RM subsets differentially co-localize with antigen presenting cells and interferon-stimulated epithelial cells along the crypt axis. By defining the make-up and tissue organization of these inflammatory “immune hubs” in the colon mucosa, we hope to shed light on how epithelial and immune interactions sustain inflammation in patients with colitis and contribute to epithelial barrier and absorptive dysfunction. The spatial organization of immune responses in tissue will be assessed with multi-spectral immunofluorescence and RNA microscopy and cutting-edge spatial transcriptomic techniques.

Determine patient-level factors that increase risk of colitis & hepatitis in individuals receiving immune checkpoint inhibitors

The risk factors for developing checkpoint colitis and hepatitis are poorly understood. Leveraging the large patient population at OHSU that is impacted by these toxicities in combination with our ability to establish a patient biorepository of matched tissue and blood samples, we seek to define the epidemiologic, genetic, circulating, and tissue-specific factors that increase versus decrease an individual’s risk of checkpoint colitis or hepatitis, including the development of steroid-refractory disease. The identification of these factors will allow for the stratification of patients at increased risk of gastrointestinal and liver irAEs and enable the development of prophylactic treatments that may prevent their development without abrogating anti-tumor immune responses. Our approach will be broadly applicable to predicting disease progression and therapy response across a broad spectrum of inflammatory human gastrointestinal and liver diseases.