Molecular basis of T cell dysfunction in cancer is influenced by the paracrine secretion of tumor-derived IL-2.
Previously we reported that T cells from mice bearing parental tumors have a variety of functional and biochemical defects when compared with T cells from mice bearing IL-2-secreting tumors. The biochemical defects included reduced levels of several cytoplasmic proteins such as p56lck, p59fyn, and zeta, all of which are known to be critical for signal transduction through the TCR. Based upon these results, we determined the consequences of these alterations on downstream signaling events. First, we showed that T cells of parental tumor-bearing mice have a reduction of total in vitro kinase activity associated with the TCR/CD3 compared with T cells from mice with IL-2-secreting tumors. Second, we observed that following activation, only T cells from IL-2-secreting tumor-bearing mice had completely phosphorylated CD3-associated zeta-chains and recruited ZAP-70 to cell surface-associated TCR. In contrast, T cells from mice with parental tumors contained incompletely phosphorylated CD3-associated zeta-chains with little or no TCR-associated ZAP-70. Third, the recruitment of ZAP-70 to the TCR/CD3 complex was seen only in animals with an increase in in vitro p56lck kinase activity after T cell activation. Finally, we report that these defects in T cell signaling were associated with generalized anergy in vivo. Our findings provide a molecular basis to explain T cell suppression of mice with parental tumors and offer a hypothesis to explain the protective effect of tumor-derived IL-2.
Salvadori
S
S
Department of Medicine, Mount Sinai School of Medicine, New York 10029, USA.
Zier
K
K
D000818:Animals; D017635:Clonal Anergy / Q000235:genetics; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000378:metabolism
D007376:Interleukin-2; D009363:Neoplasm Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D019061:src-Family Kinases