TY - JOUR
T1 - Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
AU - Kim, Sang T.
AU - Chu, Yanshuo
AU - Misoi, Mercy
AU - Suarez-Almazor, Maria E.
AU - Tayar, Jean H.
AU - Lu, Huifang
AU - Buni, Maryam
AU - Kramer, Jordan
AU - Rodriguez, Emma
AU - Hussain, Zulekha
AU - Neelapu, Sattva S.
AU - Wang, Jennifer
AU - Shah, Amishi Y.
AU - Tannir, Nizar M.
AU - Campbell, Matthew T.
AU - Gibbons, Don L.
AU - Cascone, Tina
AU - Lu, Charles
AU - Blumenschein, George R.
AU - Altan, Mehmet
AU - Lim, Bora
AU - Valero, Vincente
AU - Loghin, Monica E.
AU - Tu, Janet
AU - Westin, Shannon N.
AU - Naing, Aung
AU - Garcia-Manero, Guillermo
AU - Abdel-Wahab, Noha
AU - Tawbi, Hussein A.
AU - Hwu, Patrick
AU - Oliva, Isabella C.Glitza
AU - Davies, Michael A.
AU - Patel, Sapna P.
AU - Zou, Jun
AU - Futreal, Andrew
AU - Diab, Adi
AU - Wang, Linghua
AU - Nurieva, Roza
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-29539-3
DO - 10.1038/s41467-022-29539-3
M3 - Article
C2 - 35413951
AN - SCOPUS:85128008376
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1970
ER -