Dissecting natural killer cell education: from basic studies to improved immunotherapy of cancer

The objective of this project is define the molecular and cellular processes that control natural killer (NK) cell “education”, defined as the process by which MHC class I molecules instruct NK cell competence.In the first aim of the proposal, we use single cell RNA sequencing data to generate a molecular map of NK cell education.

Previous attempts to define its molecular control have failed.

We hypothesize that part of this failure lies in the suboptimal phenotypic and functional resolution of the input cells.

We have recently completed a single cell RNA sequencing (scRNA-seq) effort on much better defined populations with promising results that will now be followed up.In the second aim, we intend to clarify the role of the phosphatase SHP-1 in NK cell education. SHP-1 was identified as a differentially expressed gene in NK cell education, and it is in focus here.

SHP-1 is know to regulate NK cell inhibtion in a dynamic way, and studying this phoshatase offers a road to new insights.

High resolution microscopy and novel in vitro models for NK cell education will be used.In a third aim, we will test SHP-1 as a potential “dual checkpoint” for NK cell immunotherapy.

Identifying novel “druggable” target molecules that control NK cell education has the potential to function as novel checkpoint inhibitors. In this proposal, we evaluate one such candidate, SHP-1, in preclinical models for cancer therapy.