W130 - NK-like CD8 T Cells Are Essential to Immune-related Adverse Events Pathogenesis of Cancer Immunotherapy

Brian Henick, MD – Assistant Professor, Medicine, Columbia University; Robert Winchester, MD – Medicine – Columbia University; Adam Mor, MD, PhD – Assistant Professor, Medicine, Columbia University

Abstract Text: Immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4 are major game changers in cancer therapy. Nevertheless, their use is limited by the occurrence of immune-related adverse events (irAEs), which can target different organs and significantly impact the quality of life of the patients. To unravel the cellular mechanisms involved in irAEs at the protein level, we developed a T cell-specific high-dimensional panel of 42 markers for spectral flow cytometry to investigate peripheral blood T cell landscape before and during ICI treatment in patients with and without irAEs. Unsupervised cluster analysis before ICI treatment revealed that patients developing irAE have a more prominent subpopulation of CD27- CD28- PD-1- CD8+ TEMRA T cells than those without irAEs. This population is characterized by the expression of the NK markers CD56 (NCAM), NKp80 (KLRF1) and CD57. We observed a higher proportion of CD27- CD28- CD8+ T cells expressing NK cell markers in irAE patients by gating analysis.
Interestingly, these cells have been previously associated with different autoimmune diseases (e.g., rheumatoid arthritis) and effector cell phenotypes (cytotoxicity and IFNg secretion), supporting the concept that irAEs are associated with losing tolerance to self-antigens.
Current investigations aim to determine the origin of these cells and whether the lack of the canonical co-activator CD28 is compensated by the expression stress-sensing activating NK receptors, including CD56 and NKp80, and by high-self antigen reactivity. We propose a new mechanism mediating irAEs through bystander NK-like CD8 T cells, which amplify ICI-mediated tissue inflammation.