title: Reduced tumor-antigen density leads to PD-1/PD-L1-mediated impairment of partially exhausted CD8⁺ T cells.
abstract: Clinical progression of cancer patients is often observed despite the presence of tumor-reactive T cells. Co-inhibitory ligands of the B7 superfamily have been postulated to play a part in this tumor-immune escape. One of these molecules, PD-L1 (B7-H1, CD274), is widely expressed on tumor cells and has been shown to mediate T-cell inhibition. However, attempts to correlate PD-L1 tumor expression with negative prognosis have been conflicting. To better understand when PD-1/PD-L1-mediated inhibition contributes to the functional impairment of tumor-specific CD8(+)  T cells, we varied the levels of antigen density and/or PD-L1 expression at the surface of tumor cells and exposed them to CD8(+)  T cells at different levels of functional exhaustion. We found that the gradual reduction of cognate antigen expression by PD-L1-expressing tumor cells increased the susceptibility of partially exhausted T cells to PD-1/PD-L1-mediated inhibition in vitro as well as in vivo. In conclusion, chronically stimulated CD8(+)  T cells become sensitive to PD-1/PD-L1-mediated functional inhibition upon low antigen detection; a setting which is likely involved during tumor-immune escape.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Kaiser
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schuster
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.forename: Lisa
authors.initials: L
authors.lastname: Borkner
authors.forename: Henry
authors.initials: H
authors.lastname: Daebritz
authors.forename: Clemens
authors.initials: C
authors.lastname: Schmitt
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D060890:B7-H1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D015398:Signal Transduction; D018709:Statistics, Nonparametric
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D061026:Programmed Cell Death 1 Receptor