Distinct immune-effector and metabolic profile of CD8⁺ T Cells in patients with autoimmune polyarthritis induced by therapy with immune-checkpoint inhibitors

Objectives: Rheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI-therapy improves CD8 + T cell (CD8) function, but CD8 contribute to chronic inflammation in autoimmune arthritis (AA). Thus, we studied whether immune-functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients. Methods: Peripheral CD8 obtained from ICI-treated patients with and without musculoskeletal irAEs and from AA-patients with and without history of malignancy were stimulated in media containing 13 C-labeled glucose with and without Tofacitinib. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules, and inhibition of tumor cell growth were quantified. Results: CD8 from irAE patients showed significantly lower frequency and expression of cell-surface molecules characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and pro-inflammatory immune-mediators compared to CD8 from ICI-patients who did not develop irAE. This was accompanied by a lower glycolytic rate. Gene-expression analysis of pre-ICI-treated CD8 revealed over 30 differentially expressed transcripts in patients who later developed musculoskeletal irAEs. In vitro Tofacitinib treatment did not significantly change the immune-metabolic profile nor the capacity to inhibit the growth of the human lung-cancer cell-line H838. Conclusions: Our study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE have a distinct immune-effector and metabolic profile from those that remain irAE-free. This specific irAE profile overlaps with the one observed in CD8 from AA-patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs.