TY - JOUR

T1 - Exploring TCR-like CAR-Engineered Lymphocyte Cytotoxicity against MAGE-A4

AU - Alsalloum, Alaa

AU - Shevchenko, Julia

AU - Fisher, Marina

AU - Philippova, Julia

AU - Perik-Zavodskii, Roman

AU - Perik-Zavodskaia, Olga

AU - Alrhmoun, Saleh

AU - Lopatnikova, Julia

AU - Vasily, Kurilin

AU - Volynets, Marina

AU - Zavjalov, Evgenii

AU - Solovjeva, Olga

AU - Akahori, Yasushi

AU - Shiku, Hiroshi

AU - Silkov, Alexander

AU - Sennikov, Sergey

N1 - This work was carried out with the support of the Russian Science Foundation, project number 21-65-00004 (https://rscf.ru/project/21-65-00004/, accessed on 20 April 2021).

PY - 2023/10/13

Y1 - 2023/10/13

N2 - TCR-like chimeric antigen receptor (CAR-T) cell therapy has emerged as a game-changing strategy in cancer immunotherapy, offering a broad spectrum of potential antigen targets, particularly in solid tumors containing intracellular antigens. In this study, we investigated the cytotoxicity and functional attributes of in vitro-generated T-lymphocytes, engineered with a TCR-like CAR receptor precisely targeting the cancer testis antigen MAGE-A4. Through viral transduction, T-cells were genetically modified to express the TCR-like CAR receptor and co-cultured with MAGE-A4-expressing tumor cells. Flow cytometry analysis revealed a significant surge in cells expressing activation markers CD69, CD107a, and FasL upon encountering tumor cells, indicating robust T-cell activation and cytotoxicity. Moreover, immune transcriptome profiling unveiled heightened expression of pivotal T-effector genes involved in immune response and cell proliferation regulation. Additionally, multiplex assays also revealed increased cytokine production and cytotoxicity driven by granzymes and soluble Fas ligand (sFasL), suggesting enhanced anti-tumor immune responses. Preliminary in vivo investigations revealed a significant deceleration in tumor growth, highlighting the therapeutic potential of these TCR-like CAR-T cells. Further investigations are warranted to validate these revelations fully and harness the complete potential of TCR-like CAR-T cells in overcoming cancer's resilient defenses.

AB - TCR-like chimeric antigen receptor (CAR-T) cell therapy has emerged as a game-changing strategy in cancer immunotherapy, offering a broad spectrum of potential antigen targets, particularly in solid tumors containing intracellular antigens. In this study, we investigated the cytotoxicity and functional attributes of in vitro-generated T-lymphocytes, engineered with a TCR-like CAR receptor precisely targeting the cancer testis antigen MAGE-A4. Through viral transduction, T-cells were genetically modified to express the TCR-like CAR receptor and co-cultured with MAGE-A4-expressing tumor cells. Flow cytometry analysis revealed a significant surge in cells expressing activation markers CD69, CD107a, and FasL upon encountering tumor cells, indicating robust T-cell activation and cytotoxicity. Moreover, immune transcriptome profiling unveiled heightened expression of pivotal T-effector genes involved in immune response and cell proliferation regulation. Additionally, multiplex assays also revealed increased cytokine production and cytotoxicity driven by granzymes and soluble Fas ligand (sFasL), suggesting enhanced anti-tumor immune responses. Preliminary in vivo investigations revealed a significant deceleration in tumor growth, highlighting the therapeutic potential of these TCR-like CAR-T cells. Further investigations are warranted to validate these revelations fully and harness the complete potential of TCR-like CAR-T cells in overcoming cancer's resilient defenses.

KW - Humans

KW - Receptors, Chimeric Antigen/genetics

KW - T-Lymphocytes

KW - Neoplasms/metabolism

KW - Immunotherapy, Adoptive

KW - Cytotoxicity, Immunologic

KW - Receptors, Antigen, T-Cell/genetics

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85175275498&origin=inward&txGid=ba0d6a277f249ccd947318a68de67c0e

U2 - 10.3390/ijms242015134

DO - 10.3390/ijms242015134

M3 - Article

C2 - 37894816

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 20

M1 - 15134

ER -