Chemotherapy pretreatment sensitizes solid tumor-derived cell lines to V alpha 24+ NKT cell-mediated cytotoxicity.
There is an increasing awareness of the therapeutic potential for combining immune-based therapies with chemotherapy in the treatment of malignant diseases, but few published studies evaluate possible cytotoxic synergies between chemotherapy and cytotoxic immune cells. Human V alpha 24+/V beta 11+ NKT cells are being evaluated for use in cell-based immunotherapy of malignancy because of their immune regulatory functions and potent cytotoxic potential. In this study, we evaluated the cytotoxicity of combinations of chemotherapy and NKT cells to determine whether there is a potential to combine these treatment modalities for human cancer therapy. The cytotoxicity of NKT cells was tested against solid-tumor derived cell lines NCI-H358, DLD-1, HT-29, DU-145, TSU-Pr1 and MDA-MB231, with or without prior treatment of these target cells, with a range of chemotherapy agents. Low concentrations of chemotherapeutic agents led to sensitization of cell lines to NKT-mediated cytotoxicity, with the greatest effect being observed for prostate cancer cells. Synergistic cytotoxicity occurred in an NKT cell in a dose-dependent manner. Chemotherapy agents induced upregulation of cell surface TRAIL-R2 (DR5) and Fas (CD95) expression, increasing the capacity for NKT cells to recognize and kill via TRAIL- and FasL-mediated pathways. We conclude that administration of cytotoxic immune cells after chemotherapy may increase antitumor activities in comparison with the use of either treatment alone.
Mattarollo
Stephen R
SR
Centre for Immune and Targeted Therapy, University of Queensland, Greenslopes Private Hospital, Brisbane, Australia.
Kenna
Tony
T
Nieda
Mie
M
Nicol
Andrew J
AJ
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors