Tumour-induced suppression of immune response and its correction.
Immunosuppressive features of tumour cells are a major obstacle for immunotherapy of cancer. We recently noted that RENCA cells effectively interfere with the in vivo activation of RENCA-specific T cells. To unravel the underlying mechanism, we evaluated the influence of RENCA cells on a mixed-lymphocyte/ tumour reaction as well as an allogeneic mixed-lymphocyte reaction. We observed that RENCA cells were not directly immunosuppressive. Instead, they initiated deviation of an immune response in at least two independent directions: (i) expansion of a population of NK1.1+/CD3+ cells, which was accompanied by elimination of mainly CD4+ lymphocytes, and (ii) production of a leukocyte-derived inhibitory factor. Expression of the costimulatory molecule B7.1 by RENCA cells prevented induction of anergy, while expression of MHC class II molecules prevented expansion of NK1.1+ cells, which was accompanied by a significant decrease in cell death. Hence, an unimpaired response was observed only when RENCA cells expressed B7.1 plus MHC class II molecules. Thus, even if a tumour itself is not immunosuppressive, it can induce a strong deviation of the immune response. It is concluded that the first contact between elements of the immune system and the tumour cell can confer a severe bias on immunoregulatory circuits.
Department of Tumour Progression and Immune Defence, Germany Cancer Research Centre, Heidelberg.
G A
GA
Banat
O
O
Christ
B
B
Cochlovius
H B
HB
Pralle
M
M
Zöller
D000818:Animals; D000941:Antigens / Q000276:immunology; D000950:Antigens, Ly; D000954:Antigens, Surface; D017209:Apoptosis; D018122:B7-1 Antigen / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D053222:Fas Ligand Protein; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000276:immunology; D013491:Suppressor Factors, Immunologic / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D019139:Tumor Escape
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D018122:B7-1 Antigen; D017252:CD3 Complex; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D000949:Histocompatibility Antigens Class II; D007519:Isoantigens; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D013491:Suppressor Factors, Immunologic