Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response.
| العنوان: | Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response. |
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| المؤلفون: | DeGolier KR; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Danis E; Biostatistics and Bioinformatics Shared Resource, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., D'Antonio M; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Cimons J; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Yarnell M; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Center for Cancer and Blood Disorders, Children's Hospital Colorado; Aurora, CO, USA., Kedl RM; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA., Kohler ME; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Center for Cancer and Blood Disorders, Children's Hospital Colorado; Aurora, CO, USA., Scott-Browne JP; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA., Fry TJ; Department of Immunology, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.; Center for Cancer and Blood Disorders, Children's Hospital Colorado; Aurora, CO, USA. |
| المصدر: | Research square [Res Sq] 2023 Dec 21. Date of Electronic Publication: 2023 Dec 21. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101768035 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: Res Sq Subsets: PubMed not MEDLINE |
| مستخلص: | Chimeric antigen receptor T cells are an effective therapy for B-lineage malignancies. However, many patients relapse and this therapeutic has yet to show strong efficacy in other hematologic or solid tumors. One opportunity for improvement lies in the ability to generate T cells with desirable functional characteristics. Here, we dissect the biology of CD8+ CAR T cells (CAR8) by controlling whether the T cell has encountered cognate TCR antigen prior to CAR generation. We find that prior antigen experience influences multiple aspects of in vitro and in vivo CAR8 functionality, resulting in superior effector function and leukemia clearance in the setting of limiting target antigen density compared to antigen-inexperienced T cells. However, this comes at the expense of inferior proliferative capacity, susceptibility to phenotypic exhaustion and dysfunction, and inability to clear wildtype leukemia in the setting of limiting CAR+ cell dose. Epigenomic and transcriptomic comparisons of these cell populations identified overexpression of the Runx2 transcription factor as a novel strategy to enhance CAR8 function, with a differential impact depending on prior cell state. Collectively, our data demonstrate that prior antigen experience determines functional attributes of a CAR T cell, as well as amenability to functional enhancement by transcription factor modulation. Competing Interests: Additional Declarations: Yes there is potential Competing Interest. Patent applicant (whether author or institution): University of Colorado Anschutz Medical Campus Name of inventor(s): Kole R DeGolier, James P Scott-Browne, Terry J Fry Application number: U.S. Provisional Application No. 63/595,612 Status of application: Pending Aspect covered: Methods of enhancing potency of engineered immune cells via Runx2 modulation |
| معلومات مُعتمدة: | P30 CA046934 United States CA NCI NIH HHS; R01 AI151021 United States AI NIAID NIH HHS |
| تواريخ الأحداث: | Date Created: 20240110 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC10775394 |
| DOI: | 10.21203/rs.3.rs-3712137/v1 |
| PMID: | 38196657 |
| قاعدة البيانات: | MEDLINE |
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