CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer.

CD8 T cells that express retinoic acid-related orphan receptor (ROR)γt (T17 cells) have been shown to promote procarcinogenic inflammation and contribute to a tolerogenic microenvironment in tumors. We investigated their phenotype and functional properties in relationship to the pathogenesis of human distal bile duct cancer (DBDC). DBDC patients had an elevated level of type 17 immune responses and the frequency of CD8RORγt T cells (T17 cells) was increased in peripheral blood. The CD8RORγt T cells represented a highly activated subset and produced IL-17A in equal amount as CD4RORγt T cells (T17 cells). Most CD8RORγt T cells coexpressed T-bet, a lineage transcription factor for T1 and T1 development, suggesting that CD8RORγt T cells undergo plasticity toward a T17/1-like phenotype with coproduction of IL-17A and INF-γ. In comparison with CD8RORγt T cells, the CD8RORγt T cells had a higher level of TCR signaling and were terminally differentiated and exhausted. These cells also had impaired ability to re-express perforin after degranulation and reduced cytotoxic immune function. A subset of CD8RORγt T cells expressing a low level of programmed cell death protein 1 and a high level of OX40 were associated with reduced patient survival. In conclusion, CD8RORγt T cells are proinflammatory and functionally impaired and may contribute to the pathogenesis of DBDC.