Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
Sang T. Kim, Yanshuo Chu, Mercy Misoi, María E. Suarez‐Almazor, Jean Tayar, Huifang Lu, Maryam Buni, Jordan J. Kramer, Emma Rodrı́guez, Zulekha Hussain, Sattva S. Neelapu, Jennifer Wang, Amishi Y. Shah, Nizar M. Tannir, Matthew T. Campbell, Don L. Gibbons, Tina Cascone, Charles Lu, George R. Blumenschein, Mehmet Altan, Bora Lim, V. Valero, Monica Loghin, Janet Tu, Shannon N. Westin, Aung Naing, Guillermo Garcia‐Manero, Noha Abdel‐Wahab, Hussein A. Tawbi, Patrick Hwu, Isabella C. Glitza Oliva, Michael A. Davies, Sapna P. Patel, Jun Zou, P. Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva
Abstract
Abstract 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. CX3CR1 hi CD8 + T cells in blood and CXCR3 hi CD8 + T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1 hi 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.