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CHIME

CHIME (CHimeric IMmune Editing) is a CRISPR-Cas9 based delivery system that enables knockout of genes in diverse immune lineages without changing their development or function. Our goal is to use this powerful system to identify and validate regulators of responses and resistance to antitumor immunity mediated by TME-associated immune lineages. We believe this will allow the discovery and mechanistic dissection of targets that synergize with immune checkpoint blockade. In addition to target identification, we are also building new in vivo perturbation technologies to enable mechanistic dissection of novel targets using CRISPR.

 

CHIME Schematic

 

Publications:
Milling LE, Markson SC, Tjokrosurjo Q, Derosia NM, Streeter ISL, Hickok GH, Lemmen AM, Nguyen TH, Prathima P, Fithian W, Schwartz MA, Hacohen N, Doench JG, LaFleur MW, Sharpe AH. Framework for in vivo T cell screens. J Exp Med. 2024 Apr 1;221(4):e20230699. doi: 10.1084/jem.20230699. Epub 2024 Feb 27. PMID: 38411617.

LaFleur MW, Lemmen AM, Streeter ISL, Nguyen TH, Milling LE, Derosia NM, Hoffman ZM, Gillis JE, Tjokrosurjo Q, Markson SC, Huang AY, Anekal PV, Montero Llopis P, Haining WN, Doench JG, Sharpe AH. X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system. Nat Immunol. 2024 Jan;25(1):178-188. doi: 10.1038/s41590-023-01689-6. Epub 2023 Nov 27. PMID: 38012416; PMCID: PMC10881062.

LaFleur MW, Sharpe AH. CRISPR Screens to Identify Regulators of Tumor Immunity. Annu Rev Cancer Biol. 2022 Apr;6:103-122. doi: 10.1146/annurev-cancerbio-070120-094725. Epub 2021 Dec 23. PMID: 35989706; PMCID: PMC9389862.

LaFleur MW, Nguyen TH, Coxe MA, Miller BC, Yates KB, Gillis JE, Sen DR, Gaudiano EF, Al Abosy R, Freeman GJ, Haining WN, Sharpe AH. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat Immunol. 2019 Oct;20(10):1335-1347. doi: 10.1038/s41590-019-0480-4. Epub 2019 Sep 16. PMID: 31527834; PMCID: PMC6754306.

LaFleur MW, Nguyen TH, Coxe MA, Yates KB, Trombley JD, Weiss SA, Brown FD, Gillis JE, Coxe DJ, Doench JG, Haining WN, Sharpe AH. A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system. Nat Commun. 2019 Apr 10;10(1):1668. doi: 10.1038/s41467-019-09656-2. PMID: 30971695; PMCID: PMC6458184.