Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cells.
To generate tumor-specific and interferon (IFN)-gamma-producing Tc1 and Th1 cells applicable for many cancer patients, we previously developed a protocol for generating carcinoembryonic antigen (CEA)-specific Tc1 and Th1 cells from healthy human T cells by transduction with a lentivirus containing a chimeric immunoglobulin T-cell receptor (cIgTCR) gene composed of single-chain variable fragments from an anti-CEA-specific monoclonal antibody fused to an intracellular signaling domain of CD28 and CD3zeta. These cells, designated Tc1-T and Th1-T bodies, respectively, showed strong antitumor activity against CEA-expressing tumor cells in RAG2-/- mice when both of them were transferred. However, it remains unclear whether it is possible to generate Tc1-T and Th1-T bodies from cancer patients with defective T-cell function because of significant immunosuppression. Here, we prepared Tc1-T and Th1-T bodies from T cells of a colon cancer patient, and asked whether these T bodies can exert effective T-cell function against autologous tumor cells. These T bodies showed high cytotoxicity and produced IFN-gamma in response to CEA-expressing autologous tumor cells, even in the presence of soluble CEA. It was also demonstrated that Th1-T bodies supported the survival of Tc1-T bodies through cell-to-cell interactions. Furthermore, our protocol utilized retrovirus for cIgTCR transduction to achieve better induction efficiency compared to lentivirus-mediated transduction. Taken together, our findings here indicate that retrovirally transduced Tc1-T and Th1-T bodies will become a promising strategy for adoptive immunotherapy of human cancer.
Sasaki
Takeshi
T
Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Ikeda
Hiroaki
H
Sato
Masayoshi
M
Ohkuri
Takayuki
T
Abe
Hiroyuki
H
Kuroki
Masahide
M
Onodera
Masafumi
M
Miyamoto
Masaki
M
Kondo
Satoshi
S
Nishimura
Takashi
T
D002272:Carcinoembryonic Antigen / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D002678:Chimera; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D016086:Lentivirus / Q000235:genetics; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic
D002272:Carcinoembryonic Antigen; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma