Faculty, Staff and Student Publications

Publication Date

10-4-2024

Journal

Cancer Discovery

Abstract

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.

Keywords

Killer Cells, Natural, Humans, CD28 Antigens, Animals, Mice, Signal Transduction, Receptors, Chimeric Antigen, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Xenograft Model Antitumor Assays, CD3 Complex, Immunotherapy, Adoptive, Cell Line, Tumor

DOI

10.1158/2159-8290.CD-24-0096

PMID

38900051

PMCID

PMC11452288

PubMedCentral® Posted Date

4-4-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

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