title: Characterization of defective CD4-CD8- T cells in murine tumors generated independent of antigen specificity.
abstract: Immune-based therapy confers limited benefits to hosts bearing late-stage tumors. Mounting evidence points to local suppression of T cell function as the most substantial barrier to effective antitumor immunity in hosts with large tumor burdens. Despite this, events responsible for locally defective T cells and immune suppression in tumors remain unclear. We describe in this study a predominant T cell population localized within two murine tumors that is characterized by expression of apoptotic markers and TCRalphabeta/CD3, but not CD4, CD8, or NK-associated markers. These defective cells resembled double negative (DN) T cells in lpr mice, harbored defects in the expression of T cell signaling molecules, and produced the anti-inflammatory cytokine, IL-10. Conditions known to increase or decrease the accumulation of lpr DN T cells had corresponding effects on local DN tumor infiltrating lymphocyte (TIL) levels and inversely impacted host survival. Adoptive transfer into s.c. tumors demonstrated that naive CD8(+) T cells were highly susceptible to becoming DN TIL, and local supplementation of tumors with nontumor Ag-bearing MHC class I-expressing fibroblasts decreased both this susceptibility and endogenous DN TIL levels. These findings identify a major defective T cell population with suppressive potential within tumors. The data also suggest that local T cell defectiveness is controlled by the tumor environment independent of cognate Ag specificity per se. Decreasing defective DN TIL levels by increasing noncognate peptide MHC class I availability, or modulating TCR or cytokine signaling may facilitate host survival by bolstering endogenous immunity to late-stage tumors, and may help improve therapeutic tumor vaccines.
authors.affiliation: Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
authors.forename: Francesca
authors.initials: F
authors.lastname: Incardona
authors.forename: Regan
authors.initials: R
authors.lastname: Lau
authors.forename: Paul
authors.initials: P
authors.lastname: Lee
authors.forename: Sarah
authors.initials: S
authors.lastname: Claus
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wheeler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002449:Cell Aggregation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000502:physiology; D005260:Female; D005910:Glioma / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D007150:Immunohistochemistry; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D011518:Proto-Oncogene Proteins; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn