Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
Citation: Kim ST, Chu Y, Misoi M, Suarez-Almazor ME, Tayar JH, Lu H, Buni M, Kramer J, Rodriguez E, Hussain Z, Neelapu SS, Wang J, Shah AY, Tannir NM, Campbell MT, Gibbons DL, Cascone T, Lu C, Blumenschein GR, Altan M, Lim B, Valero V, Loghin ME, Tu J, Westin SN, Naing A, Garcia-Manero G, Abdel-Wahab N, Tawbi HA, Hwu P, Oliva ICG, Davies MA, Patel SP, Zou J, Futreal A, Diab A, Wang L, Nurieva R. Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy. Nat Commun. 2022 Apr 12;13(1):1970. doi: 10.1038/s41467-022-29539-3. PMID: 35413951; PMCID: PMC9005525.
Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.