2. Academic Validation
  3. Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

  • Signal Transduct Target Ther. 2023 Dec 25;8(1):457. doi: 10.1038/s41392-023-01708-w.
You Zhai # 1 2,  Yicong Du # 3,  Guanzhang Li 1 2,  Mingchen Yu 1,  Huimin Hu 1,  Changqing Pan 2,  Di Wang 2,  Zhongfang Shi 4,  Xu Yan 4,  Xuesong Li 3,  Tao Jiang 5 6 7 8 9 10,  Wei Zhang 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China.
  • 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China.
  • 3 Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, PR China.
  • 4 Department of Pathophysiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China.
  • 5 Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China. taojiang1964@163.com.
  • 6 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China. taojiang1964@163.com.
  • 7 China National Clinical Research Center for Neurological Diseases, Beijing, PR China. taojiang1964@163.com.
  • 8 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, PR China. taojiang1964@163.com.
  • 9 Research Unit of Accurate Diagnosis, Treatment, and Translational Medicine of Brain Tumors, Chinese Academy of Medical Sciences, Beijing, PR China. taojiang1964@163.com.
  • 10 Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, PR China. taojiang1964@163.com.
  • 11 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China. zhangwei_vincent@mail.ccmu.edu.cn.
  • 12 China National Clinical Research Center for Neurological Diseases, Beijing, PR China. zhangwei_vincent@mail.ccmu.edu.cn.
  • 13 Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, PR China. zhangwei_vincent@mail.ccmu.edu.cn.
  • 14 Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, PR China. zhangwei_vincent@mail.ccmu.edu.cn.
  • # Contributed equally.
PMID: 38143263 DOI: 10.1038/s41392-023-01708-w
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.

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