Human CD4+ effector T cells mediate indirect interleukin-12- and interferon-gamma-dependent suppression of autologous HLA-negative lung tumor xenografts in severe combined immunodeficient mice.
A human/severe combined immunodeficient mouse chimeric model was used to demonstrate that peripheral blood leukocytes (PBLs) from a patient with lung cancer completely suppress the growth of an autologous tumor in a PBL dose-dependent fashion repeatedly and over a 4-year period. Suppression of the patient's tumor required CD4+ T cells, CD56+ natural killer cells, and CD14+ monocytes/macrophages, but was completely independent of CD8+ T cells. The CD4+ effector cells promoted tumor killing indirectly because direct tumor recognition and killing are precluded by the absence of MHC class I and II molecules on the tumor cells. Tumor suppression was found to require both human interleukin-12 (IL-12) and IFN-gamma, which were produced and released by the patient's monocytes and T cells, respectively. These results establish that human CD4+ T cells present in the peripheral blood of a patient with lung cancer are able to orchestrate cytokine-dependent killing of an autologous MHC-negative tumor indirectly and without codependence on CD8+ T cells. We conclude that human tumor suppression is achieved in vivo even in the absence of MHC molecules on tumor cells. This tumor suppression is mediated indirectly by cytokines produced by the patient's PBLs that ultimately initiate tumor killing via several, presently incompletely defined mechanisms.
Egilmez
Nejat K
NK
Department of Microbiology, State University of New York at Buffalo, Buffalo, New York 14214, USA.
Hess
Stephen D
SD
Chen
Fang-An
FA
Takita
Hiroshi
H
Conway
Thomas F
TF
Bankert
Richard B
RB
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000276:immunology* / Q000628:therapy; D002455:Cell Division / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008175:Lung Neoplasms / Q000097:blood / Q000276:immunology* / Q000628:therapy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D006680:HLA Antigens; D018950:Lipopolysaccharide Receptors; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma