The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
Use the dropdown menu or ‘Previous’ and ‘Next’ buttons to navigate the list.
Carnevale, J., Shifrut, E. et al. Nature. 609: 174–182. (2022).
doi: 10.1038/s41586-022-05126-w.
Summary of the findings
We previously developed a strategy to enable pooled CRISPR screening in primary human T cells, enabling genome-wide queries for genes regulating key T cell functions. In this paper by Carnevale and Shifrut et al., we adapt this screening platform to model different factors that suppress T cells in the tumor microenvironment in order to identify gene targets that confer resistance to these forms of suppression. We identify RASA2, a RasGAP never before studied in immune cells, as a target gene shared across our screens. We show that RASA2 is a negative regulator of TCR stimulation and activation. RASA2 deletion increases T cell sensitivity to antigen and enhances TCR signaling responses. We find RASA2 is upregulated in the setting of chronic antigen stimulation, and that knocking out RASA2 enhances persistent effector function in the setting of repeated tumor cell exposures. RASA2 deletion alters the metabolic fitness in T cells, increasing both the spare respiratory capacity and glycolytic activity. In preclinical models both liquid and solid tumors, deletion of RASA2 in TCR-T and CAR-T cells increases tumor burden control and survival. We identify RASA2 as a new target to engineer more potent and persistent T cell therapies for cancer treatment.
Future impact
We have demonstrated the power of unbiased CRISPR screening to discover new biology in primary T cells that has direct translational implications. We identified a number of genes that regulate T cell activation and proliferation in the context of different suppressive factors that can be found in the tumor microenvironment. We show that targeted deletion of one of these genes, RASA2, generates engineered T cells with remarkable persistence in tumor killing. RASA2 is an exciting new gene target that can be manipulated in T cell therapies and holds promise for treating both liquid and solid tumors.
