Understanding and exploiting the two-faces of NK cells in checkpoint immunotherapy

Immunotherapy is particularly successful in the treatment of Metastatic Melanoma (MM). However, half of these patients do not exhibit durable survival benefit. One of the key challenges in immuno-oncology is to elucidate why this revolutionary therapeutic approach is only effective in some, but not all, patients. To begin to address this, we initiated a clinical study in MM involving 1st-line treatment with anti-PD1. Serially collected pre- and ON-treatment biopsies from 25 patients were profiled at single-cell resolution. Unexpectedly, in silico data analysis identified a population of Natural Killer (NK) cells significantly enriched in the ON-treatment biopsies from non-responders. The objective of this proposal is to determine whether this NK cell population promotes an immunosuppressive environment and, if so, how? We propose an in-depth characterization of these cells and, in particular, study their spatial distribution and surrounding cellular niches. We hypothesize that these NK cells may restrict CD8 T-cell recruitment, expansion and/or function. In particular, we will entertain the possibility that, in a fraction of patients, exposure to anti-PD1 leads to the recognition and destruction by NK cells of effector T-cells bound to the anti-PD1 antibody. These analyses may highlight a key role for NK cells in establishing an immunosuppressive tumor bed, and possibly, identify strategies to counteract their activity and, thereby, increase responsiveness to immunotherapy.