Inhibiting the inhibitor in synovial macrophages and cancer immunotherapy-associated inflammatory arthritis

The effectiveness of immune checkpoint inhibitor (ICI) therapy has transformed cancer management and enabled the possibility of long-term effective disease control. However, iatrogenic immune-related adverse events (irAEs) can limit the effectiveness of treatment.¹ Among irAEs, rheumatic manifestations are frequent and inflammatory arthritis (IA) occurs in 3–5% of patients receiving either PD-1 or combination CTLA-4 + PD-1 ICI therapy, often manifesting together with other irAEs.² Patients with IA-irAE can experience erosive disease, synovitis and joint effusion and IA-irAE can persist even after cessation of ICI therapy³.

Because ICI therapy blocks inhibitory signals of T cell activation, studies have focused on the potential role of ICI-elicited pathogenic T cells. CTLA-4 + PD-1 ICI therapy has been associated with enhanced T helper cell (Th)17 cell signatures in both synovial fluid and blood. This accumulation of Th17 parallels similar observations in psoriatic arthritis and juvenile idiopathic arthritis^4,5. However, IA-irAE has been also associated with an accumulation of type 1 interferon activated CD38^hiCD127⁻ CD8⁺ T cells in the joints and peripheral blood, which does not have correlates with other autoimmune arthropathies.⁶ While studies thus far are helping elucidate the role of T cells in IA-irAE, the participation of other immune cell subsets remains incompletely understood.

In the present study, Wood et. al. (ar-22–0514.R3) used the widely reported collagen-induced arthritis (CIA) mouse model of inflammatory arthritis to assess the role of synovial macrophages in arthritis exacerbation in response to immune checkpoint therapy. The authors show that anti-PD-L1 antibody (Ab) treatment during CIA worsens arthritis, as assessed by clinical scoring and histopathological analysis. These observations are consistent with previous studies that have demonstrated that immune checkpoints normally protect against rheumatic disease⁷ and with the emerging success of Peresolimab -a humanized IgG1 monoclonal antibody designed to stimulate the endogenous PD-1 inhibitory pathway- in rheumatoid arthritis (RA) trials.⁸

The authors conducted a comprehensive immunophenotypic analysis of cells in the joints and showed that the main cells expressing PD-L1 in the synovium are macrophages. To further validate this finding, they leveraged mice carrying myeloid-specific knockout of PD-L1 and ascertain the protective role of PD-L1-expressing cells by showing that their selective depletion worsens CIA compared with controls.

While mouse models for IA-irAE are currently under development⁹, the current paradigm is to leverage existing mouse models of IA. In this study, the choice of CIA as a first line surrogate for IA-irAE is appropriate, given the widespread use and well-documented disease features of CIA and the known role of the PD-1/PD-L1 axis in this model.¹⁰ Although the phenotype was relatively small and required large number of treatments, and prophylactic administration, this study shows that anti-PD-L1 Ab treatment enhances arthritis severity in a common model of IA. This is a significant advancement in the field of IA-irAE and it paves the way to the testing of ICI in other mouse models of IA and on backgrounds that would enable tumor implantation.

A key issue in IA-irAE is the origin of pathogenic immune cells - are they resident joint cells or circulation-derived? Here, the authors take an elegant parabiosis approach to assessing the role of circulating vs tissue resident cells. The authors surgically connected the circulation of naïve mice whose immune cells were congenically labeled with the CD45.1 marker with C57BL/6 carrying the allelic marker CD45.2. They subsequently induced CIA only in the CD45.2 parabiont. After approximately 35 days, an assessment of joint macrophages showed that there was an exchange of PD-L1⁺ synovial macrophages between the mice. Even though the CD45.1 parabiont did not develop arthritis, the results of this experiment support further investigations in the role of immune cell trafficking in the development of IA-irAE.

The authors also conducted an analysis using publicly available scRNA-seq data to determine if PD-L1⁺ macrophages are present in the human synovium, using publicly available scRNA-seq data of synovial biopsies from healthy individuals and RA patients. The analysis showed that PD-L1 gene expression in synovial macrophages was highly increased in RA vs healthy controls. PD-L1⁺ macrophages were transcriptionally distinct in which the relative gene expression for anti-inflammatory cytokines, IL10 and TGFB1 was upregulated, while pro-inflammatory cytokines were downregulated.

Understanding mechanisms of IA-irAE is important as there is an unmet need for novel therapeutics for this specific indication. Currently, glucocorticoids are often the first line. DMARDs such as methotrexate, TNF and IL6R inhibitors can also be used,^11,12 however, besides the increased risk of infections, there is concern that at least some immunosuppressants could reduce the time to cancer recurrence.^13,14 This study highlights the potential role of PD-L1⁺ synovial macrophages and lends important preliminary support to further correlational studies in humans and mechanistic studies in mouse models to validate their findings. While generalized depletion of myeloid cells by clodronate liposome treatment during disease induction in mouse models of autoimmune arthritis prevents arthritis, this approach also leads to the loss of subsets of macrophages that play an anti-inflammatory role.¹⁵ On the other hand, generalized stimulation of immune checkpoints could enhance immunosuppression and compromise the effectiveness of ICI therapy. Thus, the study also stimulates efforts in the design of precision therapeutic approaches that could selectively and locally enhance PD-L1⁺ macrophages for preventing or treating IA-irAE while minimizing effects on other pro-inflammatory macrophage populations and generalized immunosuppression.