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

Abstract

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 13C-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.

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PD-L1 blockade immunotherapy rewires cancer emergency myelopoiesis

“…Thus, our findings may also hold important implications in the emergence of irAEs observed in patients responding to ICB immunotherapy. Although activation of effector CD4 + and CD8 + T cells (55,56) as well as disturbances in Treg cells (57,58) are implicated in irAEs development, inflammatory monocytes are expected to contribute in a direct way through the secretion of pro-inflammatory cytokines and chemokines or indirectly via antigen processing and presentation. However, the role of emergency myelopoiesis in irAEs has not been examined.…”

Reduction of pro-inflammatory effector functions through remodeling of fatty acid metabolism in CD8+ T-cells from Rheumatoid Arthritis patients

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