Mechanisms of tumor evasion from NK cell surveillance and potential clinical applications
Natural Killer (NK) cells are a subset of innate lymphocytes that play a major role in the immune response against tumors. During my post-doctoral training, I discovered two mechanisms employed by tumor cells to evade NK cell-mediated immune surveillance.
Initially, we found that NK cells infiltrating tumors with low expression of MHC class I molecules became functionally anergic. NK cell anergy was associated with impaired signaling downstream of activating receptors and was reverted by treatment with pro-inflammatory cytokines. Notably, in tumors with anergic NK cells, cytokine treatment had an impressive therapeutic effect resulting in increased mouse survival (Ardolino et al., JCI, 2014).
In a second study, we discovered that NK cells in several mouse tumor models expressed the checkpoint inhibitory receptor PD-1. PD-1 inhibited the NK cell response to tumor cells expressing the PD-1 ligand PD-L1. Importantly, mice treated with a PD-1 blocking antibody responded dramatically to the treatment, with the response completely depending on the NK cells (Ardolino et al., manuscript in preparation). As PD-1 is a major target of cancer immunotherapy, this discovery is of the outmost importance and provides new insight on the successful outcome of checkpoint blockade.
During the seminar, I will present key data concerning these two studies. In addition, I will briefly overview my plan as an independent investigator, presenting some preliminary data supporting the proposal.
12 January 2016, 12:00 (Tuesday, 0th week, Hilary 2016)
Kennedy Institute of Rheumatology, Headington OX3 7FY
Bernard Sunley Lecture Theatre
Michele Ardolino (Raulet Laboratory, University of California, Berkley)
Kennedy Institute of Rheumatology
Jo Silva (NDORMS),
Wulf Forrester-Barker (University of Oxford, Nuffield Dept of Orthopaedics Rheumatology and Musculoskeletal Sciences),
Gintare Kolesnikovaite (Kennedy Institute of Rheumatology)
Organiser contact email address:
Prof Mike Dustin (PROFESSOR OF IMMUNOLOGY AND WELLCOME PRINCIPAL RESEARCH FELLOW, DIRECTOR OF RESEARCH OF THE KENNEDY INSTITUTE)
Kennedy Institute Seminars
Members of the University only