T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ) signaling mediate superior tumor regression in an animal model of adoptive cell therapy.
Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFβ), which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFβ by transduction with a TGFβ dominant negative receptor II (DN), were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-γ in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer.
Department of Surgery, University of California, Los Angeles, CA 90095, USA.
Jon G
JG
Quatromoni
Yue
Y
Wang
Dan D
DD
Vo
Lilah F
LF
Morris
Ali R
AR
Jazirehi
William
W
McBride
Talal
T
Chatila
Richard C
RC
Koya
James S
JS
Economou
D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment
D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta