Soluble PD-1 facilitates 4-1BBL-triggered antitumor immunity against murine H22 hepatocarcinoma in vivo.
OBJECTIVE
The use of costimulatory molecules targeting distinct T-cell signaling pathways has provided a means for triggering and enhancing antitumor immunity; however, it is still not fully understood what types of costimulatory molecules are suitable for the combination in tumor therapy. Our purpose in this study is to establish an effective antitumor immune approach by using costimulatory molecule 4-1BBL in combination with soluble PD-1.


METHODS
The murine H22 hepatocarcinoma served as an ectopic tumor model. Local gene transfer was done by injection with naked plasmid p4-1BBL and/or psPD-1. The synergistic mechanism of dual-gene therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment. The effects of immunotherapy were evaluated by testing the function of tumor-specific T cells, measuring tumor weight or volume, survival of mice, and H&E staining of tissues.


RESULTS
4-1BBL expressed by normal nonimmune cells effectively enhanced antitumor immune response but up-regulated PD-L1 and did not reduce IL-10 and transforming growth factor-beta (TGF-beta). sPD-1 synergized with 4-1BBL to establish efficient antitumor immune environment, including down-regulation of IL-10 and TGF-beta, further up-regulation of interleukin (IL)-2 and IFN-gamma, and higher CD8(+) T-cell infiltration. The combined treatment by 4-1BBL/sPD-1 eradicated tumors from mice with small amounts of preexistent tumor cells or tumors from approximately 60% of individuals with larger amounts of preexistent tumor cells.


CONCLUSIONS
Our findings in this report imply a great potential of 4-1BBL in combination with sPD-1 in tumor therapeutics with the in vivo existent tumor cells as antigens.
Xiao
Han
H
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Huang
Bo
B
Yuan
Ye
Y
Li
Dong
D
Han
Ling-Fei
LF
Liu
Yi
Y
Gong
Wei
W
Wu
Feng-Hua
FH
Zhang
Gui-Mei
GM
Feng
Zuo-Hua
ZH
D053330:4-1BB Ligand / Q000627:therapeutic use*; D000818:Animals; D000943:Antigens, Differentiation / Q000737:chemistry / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D006224:Cricetinae; D004357:Drug Synergism; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D008113:Liver Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000401:mortality; D061026:Programmed Cell Death 1 Receptor; D012995:Solubility; D016896:Treatment Outcome; D047368:Tumor Burden
D053330:4-1BB Ligand; D000943:Antigens, Differentiation; D019496:Cancer Vaccines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor