Tissue tropism in PD-1 therapy

PROJECT OVERVIEW

Programmed cell death protein 1 (PD1) is an immune checkpoint receptor expressed on immature thymocytes as well as peripheral CD4+ and CD8+ T cells, Natural Killer T (NKT) cells, B cells, monocytes and subsets of dendritic cells upon activation. Binding of PD-1 to its ligands PD-L1/PD-L2 plays a pivotal role in inducing self-tolerance and preventing autoreactivity through dampening effector T cells and promoting T regulatory cell development. Anti-PD1 therapy has revolutionized the treatment of many cancers. However, significant immune-related adverse events (irAEs) including colitis and rheumatic manifestations occur in many patients.

The PARIS trial which investigates a humanised antibody that binds to and agonizes PD1, aims to determine the biological effects of PD1 agonism in disease-relevant tissues (synovium, gut and salivary gland) overtime in participants with rheumatoid arthritis (RA), ulcerative colitis (UC) and Sjøgren's syndrome (SjS). By taking biopsies from target inflamed tissue pre- and post-therapy, this 'proof-of-biology' study investigates the capacity of PD1 agonism to affect T cell subsets and how this translates into ameliorating clinical and histologic findings associated with immune-mediated inflammatory diseases (IMIDs).

There is increasing appreciation that IMIDs, traditionally recognized as organ-specific with distinct pathogenicity, actually share overlapping molecular mechanisms. A greater understanding on how treatment drives tissue tropism is needed for disease prediction and prognostication, differential diagnosis, and precision medicine.

The aim of the study is to investigate the cellular changes following tissue tropism following PD-1 therapy across gut, synovium and salivary glands in RA, SjS and UC. Linking tissue tropism to therapy has thus far been limited to investigating the antagonistic properties of PD1 on its target tissue site. This study has the unique and novel opportunity to explore the shared cellular basis of tissue response by utilizing scRNA analysis of tissues pre and post PD1-agonist administration and comparing this with scRNA data from target tissue in patients with checkpoint inhibitor induced colitis, arthritis and sialadenitis. From this, we hope to better understand 1.) the role of PD1 in variability in therapeutic response between patients with an IMID as well as across IMIDs, and 2.) why a subset of patients develops irAEs following anti-PD1 therapy and not others.

In this study, we propose to apply cutting edge techniques to 1) study the postulated molecular mechanism of PD-1 in IMIDs and irAEs,2) assess whether select populations of cell types or associated differential gene expression can predict therapy response, 3) and use relevant disease models and functional studies to further validate any relevant gene modules or cell-cell interactions. This will aid better patient stratification.

The postholder must have relevant clinical training including full registration with the General Medical Council, MRCP (UK) and significant experience working within the NHS. Further, the study is expected to generate bioinformatic data at a single cell level. The appointed candidate is therefore expected to have previous experience in the use of statistical software such as R or Python. The candidate must also have a strong understanding of and evidence of previous experience in cross-institute working in clinical studies. 

KEYWORDS 

Ulcerative colitis, rheumatoid arthritis, Sjøgrens syndrome, advanced therapy, transcriptomics 

TRAINING OPPORTUNITIES 

The successful candidate will be embedded at the Kennedy Institute of Rheumatology (KIR), Oxford. The KIR is a world-leading centre in the fields of tissue biology, inflammation, and repair, with a strong emphasis on clinical translation. They will receive supervision and training by an experienced team of clinician scientists interested in the cell biology of IMIDs. They will work closely with cross-site collaborators including University Hospitals NHS Foundation Trust as well as University of Birmingham.

Specific training opportunities/benefits include:
• Histopathology, single-cell RNA-sequencing analysis, and other cutting-edge cell biology techniques available in-house.
• Strong translational environment as the study utilizes data gathered from PARIS trial.
• Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists
• Highly collaborative environment with expertise ranging from molecular and cell biology to in vivo models and computational biology / genomics analysis. 

KEY PUBLICATIONS 

1. Buckley CD, Chernajovsky L, Chernajovsky Y, et al. Immune-mediated inflammation across disease boundaries: breaking down research silos. Nat Immunol 2021;22:1344-8.
2. Sasson SC, Slevin SM, Cheung VTF, et al. Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis. Gastroenterology 2021;161:1229-44.e9.
3. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010;236:219-42.
4. Kumagai S, Togashi Y, Kamada T, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol 2020;21:1346-58.
5. Rao DA, Gurish MF, Marshall JL, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 2017;542:110-4.

THEMES 

Translational medicine, inflammation biology, IMIDs, PD-1