Immunity to cancer: attack and escape in T lymphocyte-tumor cell interaction.
Tumor cells may express antigens which are recognized in a form of HLA/peptide complexes by T cells. The frequency at which different antigens are seen by T cells of melanoma patients and healthy donors was evaluated by human leukocyte antigen (HLA)/peptide tetramer technology which stains T cells bearing the specific receptor for a given epitope. By this technique, it was found that the majority of metastatic melanoma patients can recognize differentiation antigens (particularly Melan-A/MART-1), whereas such a recognition is scanty in the early phase of the disease and in healthy subjects. Despite the presence of melanoma-specific T cells infiltrating tumor lesions, tumor rejection rarely occurs. Among the different mechanisms of such inefficient antitumor response, this review discusses the possible anti-T-cell counterattack mediated by FasL-positive tumor cells, and shows that FasL is located in the cytoplasm of melanoma cells and is transported in the tumor microenvironment through the release of melanosomes. Additionally, mechanisms of suboptimal T cell activation through tumor cell expression of peptide analogs with antagonist activity are described, together with the possibility of overcoming such anergy induction by the usage of optimized tumor epitopes. Down-modulation of HLA expression by target tumor cells and its multiple mechanisms is also considered. Finally, we discuss the role of inducible nitric oxide synthases in determining the inhibition of apoptosis in melanoma cells, which can make such tumor cells resistant to the T-cell attack.
Rivoltini
Licia
L
Units of Human Tumor Immunotherapy and Immunobiology, Istituto Nazionale Tumori, Milan, Italy.
Carrabba
Matteo
M
Huber
Veronica
V
Castelli
Chiara
C
Novellino
Luisa
L
Dalerba
Piero
P
Mortarini
Roberta
R
Arancia
Giuseppe
G
Anichini
Andrea
A
Fais
Stefano
S
Parmiani
Giorgio
G
D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D017635:Clonal Anergy / Q000276:immunology; D003593:Cytoplasm / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D053222:Fas Ligand Protein; D006680:HLA Antigens / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007157:Immunologic Surveillance / Q000276:immunology*; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D020460:Melanosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology / Q000502:physiology; D009369:Neoplasms / Q000276:immunology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006680:HLA Antigens; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019014:fas Receptor; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II