Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors.
BACKGROUND
Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies.


METHODS
Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined.


RESULTS
Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively.


CONCLUSIONS
In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.
['Matsubara|Shiro|S|0000-0002-2519-5700', 'Seki|Morinobu|M|', 'Suzuki|Shigeaki|S|', 'Komori|Takashi|T|', 'Takamori|Mikio|M|']
D000368:Aged D061067:Antibodies, Monoclonal, Humanized D000074322:Antineoplastic Agents, Immunological D001706:Biopsy D018414:CD8-Positive T-Lymphocytes D054421:Chemokine CCL21 D042783:Endothelial Cells D005260:Female D006801:Humans D008297:Male D008875:Middle Aged D018482:Muscle, Skeletal D009220:Myositis D009369:Neoplasms D000077594:Nivolumab D061026:Programmed Cell Death 1 Receptor D000072717:Tertiary Lymphoid Structures
Tertiary lymphoid organ Inflammatory myopathy PD-1 inhibitor Adverse effect Cytotoxic T cell High endothelial venule