PROJECT SUMMARY
This project focuses on how genomic regulators direct natural killer (NK) cells to control infections and
malignancies. In this regard, the specific aims are: 1) to determine mechanisms by which circulating and tissue-
resident “helper” like NK cells epigenetically remodel into each other; and, 2) identify regulatory transition points
that “lock” circulating NK cells into their cytolytic lineage, blocking the helper identities.
Natural killer cells are innate lymphocytes, which means they can recognize, and normally eliminate, infections
and tumors before a full immune response needs to be generated. This innate functionality makes them
particularly exploitable for a new generation of therapies: NK cells cannot participate in graft-versus-host disease
(important for cellular therapy), they can be armed with antibodies (required for antibody-mediated therapies),
and rapidly respond to their environment (important for cytokine therapies). Given their promise in novel anti-
cancer and immune therapeutics, a deeper understanding of clinically beneficial NK cell phenotypes is of high
priority.
Unfortunately, chronic inflammation may prevent NK cells from functioning when exploited for therapies. As such,
the goal of this proposal is to define how inflammatory environments establish NK cell identities, via epigenetic
programming. First, We will investigate how chronic inflammation alters the NK cell epigenome, shutting down
the beneficial features of NK cells used in therapy. We will then assay NK cell heterogeneity during inflammation,
including their epigenetic landscape. The output will be made available as publicly available datasets, ideally
used by many researchers to identify mechanisms governing killer NK cell identities. Indeed, as this process
may be dysfunctional in diverse pathologies, the data could be of interest to a wide range of fields. Many
infections, solid tumors and hematological malignancies, such as acute myeloid leukemia, create environments
that reprogram NK cells. Thus, the identified pathways may be a major barrier to effective immunity.