RRC ID |
56030
|
著者 |
Pan Z, Di S, Shi B, Jiang H, Shi Z, Liu Y, Wang Y, Luo H, Yu M, Wu X, Li Z.
|
タイトル |
Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein.
|
ジャーナル |
Cancer Immunol Immunother
|
Abstract |
Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1-CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3+ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC.
|
巻・号 |
67(10)
|
ページ |
1621-1634
|
公開日 |
2018-10-1
|
DOI |
10.1007/s00262-018-2221-1
|
PII |
10.1007/s00262-018-2221-1
|
PMID |
30078052
|
MeSH |
Animals
Carcinoma, Hepatocellular / immunology*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / prevention & control
Cells, Cultured
Glypicans / immunology*
Glypicans / metabolism
Humans
Immunoglobulin G / immunology*
Immunoglobulin G / metabolism
Liver Neoplasms / immunology
Liver Neoplasms / metabolism
Liver Neoplasms / prevention & control
Mice
Mice, Inbred NOD
Mice, SCID
Programmed Cell Death 1 Receptor / immunology*
Programmed Cell Death 1 Receptor / metabolism
Protein Domains
Receptors, Antigen, T-Cell / immunology*
Receptors, Antigen, T-Cell / metabolism
Recombinant Fusion Proteins / immunology*
Recombinant Fusion Proteins / metabolism
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism
Xenograft Model Antitumor Assays
|
IF |
4.9
|
引用数 |
16
|
リソース情報 |
ヒト・動物細胞 |
Huh-7 |