Objectives Immune-related adverse events (irAEs) affecting the nervous system, particularly neuromuscular disorders, are severe complications of immune checkpoint inhibitors. However, reports with neuromuscular pathology evidence remain scarce. Method We characterized the clinicopathologic features of a retrospective cohort of 42 patients with neuromuscular irAEs. Immunohistochemical analysis of CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and programmed death ligand 2 (PD-L2) expression was performed on muscle and/or nerve biopsies from 25 patients. Additionally, immunotherapy responses and clinical outcomes were followed up for prognostic analysis. Results The 42 patients had diagnoses including myositis (n = 21), peripheral neuropathy (n = 6), myasthenia gravis (n = 1), and overlapping syndromes (n = 14). The most prevalent clinical presentations were fatigue (54.8%), ptosis (52.4%), and proximal muscle weakness (52.4%). Muscle pathology exhibited a characteristic pattern of focal necrosis and inflammation with lymphocyte infiltration. PD-1 and PD-L1 were highly expressed on T lymphocytes and myofibers, and their expression was most frequently observed in the group with Common Terminology Criteria for Adverse Events grades 3–5. After follow-up for 3 to 26 months, during which immunotherapy was administered, 53.8% of patients achieved a good outcome (either complete recovery or a ≥ 2-point reduction in modified Rankin Scale score). PD-L1 (P = 0.046) and PD-L2 (P = 0.046) expression were more likely in patients with good outcomes. Conclusions The muscle pathology of neuromuscular irAEs featured focal necrosis and elevated PD-1 and PD-L1 expression on T lymphocytes and myofibers. PD-1, PD-L1, and PD-L2 expression may be associated with neuromuscular irAE severity and outcomes. <Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> Key Points • The muscle pathology of neuromuscular immune-related adverse events includes elevated PD-1 and PD-L1 expression on infiltrating T lymphocytes and muscle fibers. • PD-1, PD-L1, and PD-L2 expression are potential biomarkers for the severity and outcome of neuromuscular immune-related adverse events. </entry> </row> </tbody> </tgroup> </Table>

Muscle expression of PD1 and PD-L1 may predict the severity and outcomes of neuromuscular immune-related adverse events caused by immune checkpoint inhibitor treatment

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2025年12月27日

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Mengting Yang,
Fan Li,
Zhaoyu Chen,
Feng Gao,
Wei Zhang,
Zhaoxia Wang,
Yun Yuan,
Yawen Zhao

摘要

Objectives

Immune-related adverse events (irAEs) affecting the nervous system, particularly neuromuscular disorders, are severe complications of immune checkpoint inhibitors. However, reports with neuromuscular pathology evidence remain scarce.

Method

We characterized the clinicopathologic features of a retrospective cohort of 42 patients with neuromuscular irAEs. Immunohistochemical analysis of CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and programmed death ligand 2 (PD-L2) expression was performed on muscle and/or nerve biopsies from 25 patients. Additionally, immunotherapy responses and clinical outcomes were followed up for prognostic analysis.

Results

The 42 patients had diagnoses including myositis (n = 21), peripheral neuropathy (n = 6), myasthenia gravis (n = 1), and overlapping syndromes (n = 14). The most prevalent clinical presentations were fatigue (54.8%), ptosis (52.4%), and proximal muscle weakness (52.4%). Muscle pathology exhibited a characteristic pattern of focal necrosis and inflammation with lymphocyte infiltration. PD-1 and PD-L1 were highly expressed on T lymphocytes and myofibers, and their expression was most frequently observed in the group with Common Terminology Criteria for Adverse Events grades 3–5. After follow-up for 3 to 26 months, during which immunotherapy was administered, 53.8% of patients achieved a good outcome (either complete recovery or a ≥ 2-point reduction in modified Rankin Scale score). PD-L1 (P = 0.046) and PD-L2 (P = 0.046) expression were more likely in patients with good outcomes.

Conclusions

The muscle pathology of neuromuscular irAEs featured focal necrosis and elevated PD-1 and PD-L1 expression on T lymphocytes and myofibers. PD-1, PD-L1, and PD-L2 expression may be associated with neuromuscular irAE severity and outcomes.

Key Points

• The muscle pathology of neuromuscular immune-related adverse events includes elevated PD-1 and PD-L1 expression on infiltrating T lymphocytes and muscle fibers.

• PD-1, PD-L1, and PD-L2 expression are potential biomarkers for the severity and outcome of neuromuscular immune-related adverse events.