Moderate expression of CD39 in GPC3-CAR-T cells shows high efficacy against hepatocellular carcinoma

• Published in: Frontiers of medicine Vol. 18; no. 4; pp. 708 - 720
• Main Authors: Zou, Fan, Wei, Jialiang, Zhuang, Jialang, Liu, Yafang, Tan, Jizhou, Huang, Xianzhang, Liu, Ting
• Format: Journal Article
• Language: English
• Published: Beijing Higher Education Press 01-08-2024; Springer Nature B.V
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Apyrase - genetics; Apyrase - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Glypicans - genetics; Glypicans - immunology; Glypicans - metabolism; Humans; Immunotherapy, Adoptive - methods; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - immunology; Liver Neoplasms - therapy; Lymphocytes; Medicine; Medicine & Public Health; Mice; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Research Article; Xenograft Model Antitumor Assays; CD39; mdivi-1; antitumor activity; CAR-T cells; hepatocellular carcinoma
• ISSN: 2095-0217; 2095-0225; 2095-0225
• DOI: 10.1007/s11684-024-1071-9

CD39 serves as a crucial biomarker for neoantigen-specific CD8
+
T cells and is associated with antitumor activity and exhaustion. However, the relationship between CD39 expression levels and the function of chimeric antigen receptor T (CAR-T) cells remains controversial. This study aimed to investigate the role of CD39 in the functional performance of CAR-T cells against hepatocellular carcinoma (HCC) and explore the therapeutic potential of CD39 modulators, such as mitochondrial division inhibitor-1 (mdivi-1), or knockdown CD39 through short hairpin RNA. Our findings demonstrated that glypican-3-CAR-T cells with moderate CD39 expression exhibited a strong antitumor activity, while high and low levels of CD39 led to an impaired cellular function. Methods modulating the proportion of CD39 intermediate (CD39
int
)-phenotype CAR-T cells such as mdivi-1 and CD39 knockdown enhanced and impaired T cell function, respectively. The combination of mdivi-1 and CD39 knockdown in CAR-T cells yielded the highest proportion of infiltrated CD39
int
CAR-T cells and demonstrated a robust antitumor activity
in vivo.
In conclusion, this study revealed the crucial role of CD39 in CAR-T cell function, demonstrated the potential therapeutic efficacy of combining mdivi-1 with CD39 knockdown in HCC, and provided a novel treatment strategy for HCC patients in the field of cellular immunotherapy.