Study builds comprehensive molecular resource for personalizing NK cell therapy for blood cancers

RESEARCH SUMMARY

Study Title: Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Publication: Immunity, December 12, 2023

Dana-Farber Cancer Institute author: Constantine S. Mitsiades, PhD

Summary:

Natural killer (NK) cells are an emerging immunotherapy, particularly in blood cancers. However, cancer cells can evade NK cell attacks and limit their effectiveness against cancer. Researchers from Dana-Farber Cancer Institute and University of Helsinki examined the ways that NK cells and a broad range of blood cancer cells change when they interact to learn what molecules give NK cells an advantage or disadvantage. Using single cell RNA-sequencing, which reveals which genes are activated at a given time in the cell, they learned that NK cells don’t react the same way to all cancer cells. Using CRISPR screens, which enabled them to systematically turn on and off the genes in the cancer cells, they were able to identify which genes help cancer cells evade NK cells, and which make them more vulnerable. Some of the proteins made by genes they found to be related to resistance could be targeted by drugs to improve NK cell effectiveness. Overall, this comprehensive study found a diversity of mechanisms influencing susceptibility to NK cell therapy across different cancers, including leukemias, lymphomas, and myelomas, and suggests that cancer subtypes and genetics should be considered in efforts to personalize NK cell-based therapies.

Impact:

NK cells are a promising approach to immunotherapy but cancers often develop resistance. This study provides a comprehensive picture of the molecular changes happening in NK and blood cancer cells when they interact and highlights the underlying mechanisms of sensitivity and resistance to NK cell therapy. This is an important resource for investigators developing new personalized NK cell immunotherapies.

Funding:

The collaboration of the labs of Dr Mustjoki and Mitsiades has been supported by grants from the Leukemia and Lymphoma Society (LLS) Translational Research Program and programs of the National Institutes of Health in the US and the Research Council of Finland.

The studies conducted by the Mitsiades Lab in Boston were also supported by Stand Up To Cancer (SU2C), de Gunzburg Myeloma Research Fund, Ludwig Center at Harvard, International Myeloma Society, Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research, Cobb Family Myeloma Research Fund, and the Lauri Strauss Leukemia Foundation.