PMC5827159_01
Temporal artery biopsy of the case report patient showing transmural inflammation of the adventitial, medial, and intimal layers with a fragmented internal and external lamina elastic (white arrows) (Verhoeff-Van Gieson staining).
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F1
On May 23, 2016, the patient underwent a temporal artery biopsy from his right temporal artery, which revealed a transmural inflammation of the adventitial, medial, and intimal layers of the temporal artery with a fragmented internal and external lamina elastic, diagnostic for GCA (Figure 1).
Timeline of events leading to the development of GCA induced by checkpoint immunotherapy. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GC, glucocorticoids; GCA, giant cell arteritis; ICI, immune checkpoint inhibitor. Surgery included a modified radical dissections including a parotidectomy, a neck dissection, and a free skin transplantation on June 8, 2015, for stage IIIb melanoma, which was followed by inclusion in the CA209-238 study [Efficacy Study of Nivolumab Compared to Ipilimumab in Prevention of Recurrence of Melanoma After Complete Resection of Stage IIIb/c or Stage IV Melanoma (CheckMate 238);  number, NCT02388906].
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F2
A schematic representation of GCA development induced by immune checkpoint blockade is given in Figure 2.
Schematic model of the pathogenesis of giant cell arteritis, facilitated by the state of chronic inflammation in aged individuals and in addition by an overactivated immune system triggered by immune checkpoint inhibitor treatment. The inflammatory response in the arterial wall is initiated when resident dendritic cells (DCs) sense danger signals via pattern recognition receptors such as toll-like receptors. Activated DCs produce chemokines (CCL18, CCL19, CCL20, and CCL21), which recruit CD4+ T cells; once recruited in the arterial wall, CD4+ T cells are activated by DCs presenting still undefined antigen(s). The presence of pro-inflammatory cytokines (IL-6, IL-1beta, IL-23, IL-18, and IL-12) in the microenvironment polarizes CD4+ T cells toward Th1 and Th17 cells, which produce large amounts of IFN-gamma and IL-17. Eventually, monocytes enter the vascular wall and differentiate into macrophages promoting vascular inflammation by secreting cytokines and vascular damage via secretion of matrix metalloproteinases (MMPs). Macrophages, giant cells or injured VSMC also produce growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). This results in vascular remodeling: intimal hyperplasia and vessel occlusion. The whole process is facilitated by a state of chronic inflammation as observed in aged individuals and additionally by an overactivated immune system triggered by immune checkpoint therapy treatment in this case.
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F3
The case described above is a prime example of an adverse consequence upon immune checkpoint therapy, illustrating that removing the natural brakes of the immune system may lead to a breach of tolerance and development of autoimmunity, such as LVV in this example (Figure 3).