title: Thymosin alpha1 enhanced cytotoxicity of iNKT cells against colon cancer via upregulating CD1d expression.
abstract: Increasing evidence showed invariant NKT cells (iNKT cell) are an attractive candidate for cancer immunotherapy, but its role in colorectal cancer treatment was still unclear. Here we reported iNKT cells exerted moderate cytotoxic effect against colorectal cancer cells (CRC cells) with the stimulation of α-Galcer, and the mutual recognition between CRC and iNKT cells could be greatly enhanced by Thymosinα1 (TA), which resulted in stronger killing efficiency both in vitro and in vivo. TA is widely used as an immune adjuvant for cancer therapy, but how it works on cancer cells still remains unclear. We found TA could upregulate CD80, B7H2 and CD1d expression on CRC cells. However, neutralization assay revealed iNKT cells' activation depended on CD1d expression rather than CD80 or B7H2. Moreover, colon cancer stem cells expressed higher CD1d level, which accounted for their greater sensitization to iNKT cells. Mechanistically, inhibition of Erk/MAPK pathway greatly attenuated the upregulation of CD1d by TA. Taken together, depending on Erk/MAPK pathway, TA promoted the activation and cytotoxicity of iNKT cells via upregulating CD1d expression on CRC cells, which indicated a novel immunotherapeutic strategy of iNKT cells against CRC.
authors.affiliation: Department of General Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, China; Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ni
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Wu
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Department of Clinical Laboratory, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Xianguo
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology (Cancer Center), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Chest Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Department of Oncology (Cancer Center), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Fuming
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Department of Oncology (Cancer Center), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: drhuangjian@zju.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055611:Natural Killer T-Cells / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D055610:Antigens, CD1d; D000970:Antineoplastic Agents; C526877:CD1D protein, human; D012333:RNA, Messenger; D013947:Thymosin; D000077596:Thymalfasin
keywords: CD1d; Cancer stem cells; Colon cancer; Invariant NKT cells; Thymosin alpha 1