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

Abstract

ObjectivesRheumatic 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 contributes to chronic inflammation in autoimmune arthritis (AA). Thus, we investigated whether immune functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients.MethodsPeripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing 13C-labelled glucose with and without tofacitinib or infliximab. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules and inhibition of tumour cell growth were quantified.ResultsCD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838.ConclusionsOur study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has 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.

Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature

“…ICI affect T cell immune function. T cells infiltrate the organ and cause an immune activation response ( 5 , 6 ), which destroys pancreatic beta cells and leads to absolute insulin deficiency, namely type 1 diabetes. Type 1 diabetes can be divided into delayed type 1 diabetes, acute type 1 diabetes, or fulminant type 1 diabetes.…”

Seronegative rheumatoid arthritis: one year in review 2023

“…Arthritis in course of ICIs is mostly polyarticular and seronegative in 80% of the cases, thus hardly distinguishable from seronegative RA (34). Pathogenetically, ICIs can induce Th17 cell activation and proliferation, changes in CD8 immune-effectors profile, and impaired regulatory T cell survival (35,36). A specific role of the IL-17 axis also in seronegative RA, if any, remains to be investigated.…”

Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

“…A recent molecular study demonstrated that CD8 + T cells from ICI-treated patients who developed arthritis had distinct effector functions and metabolic profiles from those from ICI-treated patients who remained arthritis-free and that TNF-α inhibitors or Janus kinase (JAK) inhibitors were unable to adequately correct such dysfunction in vitro [ 98 ]. This suggests that bDMARDs and JAK inhibitors may effectively reduce symptoms but may not fundamentally restore T cell function, although because of the risk of malignancy [ 99 ], JAK inhibitors are normally avoided in ICI-induced arthritis.…”