Related Experiment Video
Updated: Jul 7, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape
You Zhai1,2, Yicong Du3, Guanzhang Li1,2
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China.
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors. Although instances of rapid tumor remissions have been observed in animal models and clinical trials, tumor relapses occur with multiple therapeutic resistance mechanisms. Furthermore, while the mechanisms underlying the long-term therapeutic resistance are well-known, short-term adaptation remains less understood. However, more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance. In this study, we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells, a reversal of previously documented processes. This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction, also leading to short-term antigen loss and antigen masking. Such type of intercellular communication is independent of CAR downstream signaling, CAR-T cell condition, target antigen, and tumor cell type. However, it is mainly dependent on antigen density and CAR sensitivity, and is associated with tumor cell cholesterol metabolism. Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities. Together, our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.
Insights
Tumor cells can steal chimeric antigen receptor (CAR) molecules from CAR-T cells via trogocytosis, causing CAR-T cell dysfunction and treatment resistance. This novel mechanism highlights a new therapeutic target for improving CAR T-cell therapy efficacy.
Area of Science:
- Immunotherapy
- Cellular Biology
- Oncology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematologic malignancies and solid tumors.
- Tumor relapse and therapeutic resistance are significant challenges in CAR T-cell therapy.
- Short-term tumor adaptation mechanisms contributing to resistance are not fully understood.
Purpose of the Study:
- To investigate a novel mechanism of short-term adaptation in CAR T-cell therapy.
- To explore tumor cell-mediated transfer of CAR molecules from CAR-T cells.
- To understand the implications of this transfer on CAR T-cell function and therapeutic resistance.
Main Methods:
- Investigated trogocytosis as a mechanism for CAR molecule acquisition by tumor cells.
- Analyzed the impact of CAR molecule transfer on CAR-T cell dysfunction.
- Assessed factors influencing trogocytosis, including antigen density and CAR sensitivity.
- Explored the role of tumor cell cholesterol metabolism.
Main Results:
- Discovered that tumor cells acquire CAR molecules from CAR-T cells through trogocytosis.
- This process leads to CAR molecule depletion, CAR-T cell dysfunction, and short-term antigen loss/masking.
- Trogocytosis is independent of CAR signaling and cell types but dependent on antigen density and CAR sensitivity.
- Tumor cell cholesterol metabolism is associated with this trogocytosis-induced transfer.
Conclusions:
- Identified trogocytosis as a previously unreported mechanism of CAR T-cell resistance.
- This finding refines the understanding of short-term tumor adaptation in CAR T-cell therapy.
- Suggests strategies for mitigating trogocytosis, such as individualizing CAR-T cell sensitivity to tumor antigen density, to improve clinical outcomes.
Related Concept Videos
01:27Tumor Immunotherapy
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...