Reduced tumor‐antigen density leads to PD‐1/PD‐L1‐mediated impairment of partially exhausted CD8+ T cells

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.