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.