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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
CD58 loss in tumor cells confers functional impairment of CAR T cells
Xin Yan1,2, Deyun Chen1, Xinran Ma1,2
1Department of Bio-therapeutic, the First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in treating a variety of hematologic malignancies, but resistance to this treatment in some patients limited its wider application. Using an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screening, we identified and validated loss of CD58 conferred immune evasion from CAR T cells in vitro and in vivo. CD58 is a ligand of the T-cell costimulatory molecule CD2, and CD58 mutation or downregulated expression is common in hematological tumors. We found that disruption of CD58 in tumor cells induced the formation of suboptimal immunological synapse (IS) with CAR T cells, which conferred functional impairment of CAR T cells, including the attenuation of cell expansion, degranulation, cytokine secretion, and cytotoxicity. In summary, we describe a potential mechanism of tumor-intrinsic resistance to CAR T-cell therapy and suggest that this mechanism may be leveraged for developing therapeutic strategies to overcome resistance to CAR T-cell therapy in B-cell malignancies.
Insights
Loss of CD58 on tumor cells allows immune evasion from chimeric antigen receptor (CAR) T-cell therapy by disrupting the immunological synapse. This finding reveals a resistance mechanism and suggests new strategies for treating hematologic malignancies.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematologic malignancies.
- Treatment resistance limits the wider application of CAR T-cell therapy.
Purpose of the Study:
- To identify mechanisms of tumor-intrinsic resistance to CAR T-cell therapy.
- To investigate the role of CD58 in CAR T-cell immune evasion.
Main Methods:
- Genome-wide CRISPR/Cas9 screening to identify genes conferring resistance.
- In vitro and in vivo validation of identified resistance mechanisms.
- Analysis of immunological synapse formation and CAR T-cell function.
Main Results:
- Loss of CD58 was identified as a mechanism of immune evasion from CAR T cells.
- CD58 disruption impaired CAR T-cell function, including expansion, degranulation, cytokine secretion, and cytotoxicity.
- Tumor cell CD58 loss induced suboptimal immunological synapse formation.
Conclusions:
- CD58 loss represents a tumor-intrinsic resistance mechanism to CAR T-cell therapy.
- Targeting CD58 or related pathways may overcome resistance in B-cell malignancies.
- Understanding this mechanism can inform the development of novel therapeutic strategies.
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