Distinct immune-effector and metabolic profile of CD8+ T Cells in patients with autoimmune polyarthritis induced by therapy with immune-checkpoint inhibitors
Authors: Benesova Karolina , Kraus Franziska V. , Carvalho Rui A. , Diekmann Leonore , Günther Janine , Klika Karel D. , Christopoulos Petros , Hassel Jessica C. , Lorenz Hanns-Martin , Souto-Carneiro M Margarida 
Published: March 2022

AbstractObjectivesRheumatic 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.MethodsPeripheral 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.ResultsCD8 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.ConclusionsOur 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.Key messagesWhat is already known about this subject?Immune-checkpoint inhibition (ICI) therapies have a high success rate regarding progression free and overall survival of cancer patients. However, up to 20% of the ICI-treated patients develop musculoskeletal immune-related adverse events (irAE) that are often associated with severely reduced quality of life.To avoid precocious ICI-treatment termination, strategies to treat rheumatic irAE have to be simultaneously efficient in curbing musculoskeletal symptoms without interfering with the antitumoral therapy.CD8+ T cells play a pivotal role both in arthritis pathogenesis and antitumoral responses.What does this study add?Immuno-functional and metabolic analysis of peripheral CD8+ T cells from patients with musculoskeletal irAEs revealed that they share a common profile with those from patients with chronic autoimmune polyarthritis (AA) but are distinct from ICI-treated patients who remained irAE-free.CD8+ T cells from irAE patients treated in vitro with the JAK-pathway inhibitor Tofacitinib still maintained the capacity to release cytokines and cytolytic molecules, express immune-effector cell surface molecules, and prevent the growth of a human lung-cancer cell line.How might this impact on clinical practice or future developments?The specific immuno-functional and metabolic profile in rheumatic irAEs and its overlap to AA-profile is a potential starting point for a better understanding of the pathogenesis and identification of ICI-patients at risk of developing an irAE.JAK inhibitors may expand the thus far limited therapeutic armamentarium to cope with severe, refractory and / or chronical rheumatic irAEs.