title: Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model.
abstract: Mechanisms of self-tolerance often result in CD8(+) tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8(+) T cells became tolerized in <24 h in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8(+) T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first molecular profile of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells.
authors.affiliation: University of Colorado School of Medicine, Aurora, CO 80045; and.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Waugh
authors.affiliation: Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Leach
authors.affiliation: University of Colorado School of Medicine, Aurora, CO 80045; and.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Moore
authors.affiliation: University of Colorado School of Medicine, Aurora, CO 80045; and.
authors.forename: Tullia C
authors.initials: TC
authors.lastname: Bruno
authors.affiliation: University of Colorado School of Medicine, Aurora, CO 80045; and.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Buhrman
authors.affiliation: University of Colorado School of Medicine, Aurora, CO 80045; and jill.slansky@ucdenver.edu.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Slansky
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D059014:High-Throughput Nucleotide Sequencing; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D019139:Tumor Escape / Q000276:immunology*