Adoptively transferred ex vivo expanded gammadelta-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer.
In contrast to antigen-specific alphabeta-T cells (adaptive immune system), gammadelta-T cells can recognize and lyse malignantly transformed cells almost immediately upon encounter in a manner that does not require the recognition of tumor-specific antigens (innate immune system). Given the well-documented capacity of gammadelta-T cells to innately kill a variety of malignant cells, efforts are now actively underway to exploit the antitumor properties of gammadelta-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of gammadelta-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively transferred gammadelta-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled gammadelta-T cells, we first show that adoptively transferred gammadelta-T cells localize to breast tumors in a mouse model (4T1 mammary adenocarcinoma) of human breast cancer. Moreover, by using an antibody directed against the gammadelta-T cell receptor (TCR), we determined that localization of adoptively transferred gammadelta-T cells to tumor is a TCR-dependant process. Additionally, biodistribution studies revealed that adoptively transferred gammadelta-T cells traffic differently in tumor-bearing mice compared to healthy mice with fewer gammadelta-T cells localizing into the spleens of tumor-bearing mice. Finally, in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, we demonstrate that adoptively transferred gammadelta-T cells are both effective against breast cancer and are otherwise well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively transferred gammadelta-T cells as a form of cell-based immunotherapy for the treatment of breast cancer. Additionally, these studies establish that clinically applicable methods for radiolabeling gammadelta-T cells allows for the tracking of adoptively transferred gammadelta-T cells in tumor-bearing hosts.
Beck
Benjamin H
BH
Department of Medicine, Division of Hematology and Oncology, University of Alabama at Birmingham, SHEL 571, 1825 University Boulevard, Birmingham, AL 35294, USA.
Kim
Hyung-Gyoon
HG
Kim
Hyunki
H
Samuel
Sharon
S
Liu
Zhiyong
Z
Shrestha
Robin
R
Haines
Hilary
H
Zinn
Kurt
K
Lopez
Richard D
RD
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor / Q000637:transplantation; D002634:Chemotaxis, Leukocyte; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013154:Spleen / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014183:Transplantation, Heterologous; D014185:Transplantation, Isogeneic
D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D016692:Receptors, Antigen, T-Cell, gamma-delta