Protective immunosurveillance and therapeutic antitumor activity of gammadelta T cells demonstrated in a mouse model of prostate cancer.
In contrast to Ag-specific alphabeta T cells, gammadelta T cells can kill malignantly transformed cells in a manner that does not require the recognition of tumor-specific Ags. Although such observations have contributed to the emerging view that gammadelta T cells provide protective innate immunosurveillance against certain malignancies, particularly those of epithelial origin, they also provide a rationale for developing novel clinical approaches to exploit the innate antitumor properties of gammadelta T cells for the treatment of cancer. Using TRAMP, a transgenic mouse model of prostate cancer, proof-of-concept studies were performed to first establish that gammadelta T cells can indeed provide protective immunosurveillance against spontaneously arising mouse prostate cancer. TRAMP mice, which predictably develop prostate adenocarcinoma, were backcrossed with gammadelta T cell-deficient mice (TCRdelta(-/-) mice) yielding TRAMP x TCRdelta(-/-) mice, a proportion of which developed more extensive disease compared with control TRAMP mice. By extension, these findings were then used as a rationale for developing an adoptive immunotherapy model for treating prostate cancer. Using TRAMP-C2 cells derived from TRAMP mice (C57BL/6 genetic background), disease was first established in otherwise healthy wild-type C57BL/6 mice. In models of localized and disseminated disease, tumor-bearing mice treated i.v. with supraphysiological numbers of syngeneic gammadelta T cells (C57BL/6-derived) developed measurably less disease compared with untreated mice. Disease-bearing mice treated i.v. with gammadelta T cells also displayed superior survival compared with untreated mice. These findings provide a biological rationale for clinical trials designed to adoptively transfer ex vivo expanded autologous gammadelta T cells for the treatment of prostate cancer.
Liu
Zhiyong
Z
Division of Hematology and Oncology, Department of Pathology, The Univeresity of Alabama at Birmingham, 1900 University Boulevard, Birmingham, AL 35294, USA.
Eltoum
Isam-Eldin A
IE
Guo
Ben
B
Beck
Benjamin H
BH
Cloud
Gretchen A
GA
Lopez
Richard D
RD
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007157:Immunologic Surveillance; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D014185:Transplantation, Isogeneic
D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta