Elucidating immune processes in tumors that affect patient survival and response to therapy

Over the last decade, we have witnessed a major advance in immunotherapy for human cancer patients with immune checkpoint inhibitor (ICI) treatment. An unfortunate side effect of these therapies is the development of immune-related adverse events (irAE). Currently, it is not known whether development of irAE can be uncoupled from successful cancer therapy.

To develop molecular markers of irAE development, we are investigating antigen-specific T cells in ICI-treated cancer patients, in collaboration with Drs. Erik Wambre and Jane Buckner at BRI, Dr. JP Flores at Virginia Mason Medical Center, and Dr. Petros Grivas at the Fred Hutchinson Cancer Research Center. The central hypothesis for this project is that ICI blockade promotes the proliferation and survival of T cells specific for self-antigens that ultimately contributing to adverse immune events.

Linsley Lab Res Proj Inline - Elucidating Immune Processes
Identifying clonally expanded TAA reactive CD8+ T cells in peripheral blood of a checkpoint inhibitor treated cancer patient. Individual dots are cells pooled from visits before and after ICI therapy, colored by cluster of shared gene expression as measured by scRNA-seq. Blue two-dimensional density plots indicate locations of clonally expanded TAA reactive CD8+ T cells sharing identical TCR sequences. Provided by E. Wambre, Maochang Liu, Hannah DeBerg and Peter Linsley, unpublished.

Our objective is to determine if expansion of autoreactive cells predicts development of autoimmunity and/or efficacy of ICI therapy. We are recruiting cancer patients who are receiving ICI therapy and testing for linkage between the frequency and phenotypes of tumor and autoimmune antigen reactive cells in patient samples collected before and after treatment. An example of our approach is shown in the above figure, where we have profiled CD8+ T cells recognizing Tumor Associated Antigens (TAA) by scRNA-seq before and after ICI therapy. We are investigating how these TAA-specific CD8+ T cells are linked to response to therapy and development of irAEs.