Journal
CELL METABOLISM
Volume 34, Issue 4, Pages 595-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2022.02.009
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Funding
- NIH/NCI/NIDA [DP2CA238295, R01CA231112, U54CA209992-8697, R33CA225498, RF1DA048811, P50CA196530-A10805, P50CA121974-A08306]
- DOD [W81XWH-17-1-0235, W81XWH-20-1-0072, W81XWH-21-1-0514]
- Melanoma Research Alliance [412806, 16-003524]
- St. Baldrick's Foundation [426685]
- Breast Cancer Alliance
- Cancer Research Institute (CLIP)
- AACR [499395, 17-20-01-CHEN]
- Mary Kay Foundation [017-81]
- V Foundation [V2017-022]
- Alliance for Cancer Gene Therapy
- Sontag Foundation (DSA)
- Pershing Square Sohn Cancer Research Alliance
- Blavatnik Family Foundation
- NIH/NIAID Human Immunology Project Consortium (HIPC) program [U19AI089992]
- Yale MSTP training grant from the NIH [T32GM007205]
- NIH/NCI fellowship [F30CA250249]
- Revson Post-doctoral Fellowship
- Yale SBI/Genetics Startup Fund
- Damon Runyon Dale Frey Award [DFS-13-15]
- Ludwig Family Foundation
- Chenevert Family Foundation
- CRI Irvington Postdoctoral Fellowship
- R.J. Anderson Postdoctoral Fellowship
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This study developed a dgRNA-based CRISPR activation screen to identify gain-of-function (GOF) targets for CAR-T engineering. Enhancing PRODH2 expression improved the killing ability and in vivo efficacy of CAR-T cells against cancer. Metabolic and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells.
Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knockin or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression reshaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic, and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together, these findings provide a system for identification of GOF immune boosters and demonstrate PRODH2 as a target to enhance CAR-T efficacy.
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