The Antitumor Activity of CAR-T-PD1 Cells Enhanced by HPV16mE7-Pulsed and SOCS1-Silenced DCs in Cervical Cancer Models

• Main Authors: Zheng J, Huang J, Ma W, Yang W, Hu B
• Format: Article
• Language: English
• Published: Dove Medical Press 2021-08-01
• Series: Cancer Management and Research
• Subjects: pd1/pdl1; car-t; dendritic cells; suppressor of cytokine signaling 1; cervical cancer
• Online Access: https://www.dovepress.com/the-antitumor-activity-of-car-t-pd1-cells-enhanced-by-hpv16me7-pulsed--peer-reviewed-fulltext-article-CMAR

Jingwei Zheng,1,* Jingsong Huang,2,* Wei Ma,3 Wenqiang Yang,3 Bicheng Hu3 1Clinical Medical College of Jilin University, Changchun, 130012, People’s Republic of China; 2Department of Transfusion, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, People’s Republic of China; 3The Central Laboratory, Wuhan No.1 Hospital, the Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan, 430022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bicheng HuThe Central Laboratory, Wuhan No.1 Hospital, the Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan, 430022, Hubei, People’s Republic of ChinaTel/Fax [phone]Email [e-mail]: Genetically T cells modified with cancer-specific chimeric antigen receptors (CARs) showed great promise in mediate tumor regression, especially in patients with advanced leukemia. However, the therapeutic effect against solid tumors is not as prominent as anticipated to exhibit potent antitumor efficacy. The underlying mechanism maybe attributed to the inhibitory co-stimulatory pathways such as (PD1/PDL1), which provide tumor cells an escape mechanism from immunosurveillance. Therefore, by exchanging the transmembrane and cytoplasmic tail of PD1 with positive costimulatory molecules, such as CD28 and 4– 1BB signaling domains (PD1-CD28-4-1BB, PD1-CAR), the T cell-negative co-stimulatory PD1/PDL1 signal pathway was thus converted into a positive one. This study aimed to investigate whether the genetically modified CAR-T-PD1 cells activated by SOCS1 silenced DCs have enhanced anti-neoplastic potential in vitro/in vivo.Methods: In order to enhance the antigenicity and reduce transformation activity, a modified HPV16 E7 (HPV16mE7) was employed to load on dendritic cells (DCs) with SOCS1 silenced to improve its antitumor efficiency and targeting ability against cervical cancer. The CAR-T-PD1 cells activated by the generated DCs were transfused into murine models bearing tumor of CaSki cells that expressing PDL1 and HPV16 E6/E7 for in vitro/in vivo antitumor activity assay.Results: The data showed that DC-activated CAR-T-PD1 cells significantly increased the secretion of IL-2, IFN-γ and TNF-α, whilst enhanced cytotoxic activity, suppressed tumor growth and prolong the survival time compared with the controls.Conclusion: These results indicated that the genetically engineered T cells activated by DCs had improved antitumor efficiency and targeting ability. Furthermore, it was suggested that it may have important implications for the improvement of T cell immunotherapy against cervical cancer.Keywords: PD1/PDL1, CAR-T, dendritic cells, suppressor of cytokine signaling 1, cervical cancer