PT  - JOURNAL ARTICLE
AU  - Emily F. Davis-Marcisak
AU  - Allison A. Fitzgerald
AU  - Michael D. Kessler
AU  - Ludmila Danilova
AU  - Elizabeth M. Jaffee
AU  - Neeha Zaidi
AU  - Louis M. Weiner
AU  - Elana J. Fertig
TI  - A novel mechanism of natural killer cell response to anti-CTLA-4 therapy identified by integrative analysis of mouse and human tumors
AID  - 10.1101/2020.05.31.125625
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.31.125625
4099  - http://biorxiv.org/content/early/2020/05/31/2020.05.31.125625.short
4100  - http://biorxiv.org/content/early/2020/05/31/2020.05.31.125625.full
AB  - Immune checkpoint-inhibitory antibodies (ICIs) are well-established immunotherapies. Despite this, the impact of ICI therapy on non-T cell intratumoral immune cells is ill-defined, restraining the improvement of ICI efficacy. Preclinical murine models of human disease are infrequently validated in clinical trials, impairing the identification of novel biological factors impacting clinical ICI response. To address this barrier, we used our previously described computational approach that integrates high-throughput single-cell RNA sequencing datasets to identify known and novel cellular alterations induced by ICIs that are conserved in mice and humans. We found a signature of intratumoral natural killer (NK) cell activation that is enriched in anti-CTLA-4 treated mouse tumors and correlates with longer overall survival and is predictive of anti-CTLA-4 (ipilimumab) response in melanoma patients. We demonstrate that human NK cells express CTLA-4, which directly binds anti-CTLA-4. These data reveal a novel role for NK cells in anti-CTLA-4 treatment and present opportunities to enhance ICI efficacy. Importantly, we provide a new computational tool for onco-immunology that can identify and validate biological observations across species.Competing Interest StatementThe authors have declared no competing interest.