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Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures
Laurene S Cheung1,2, Lingling Chen1,2, Teniola F Oke1,2
1Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA.
Abstract:
Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.
Insights
Undifferentiated pleomorphic sarcoma (UPS) in the head and neck may respond to PD-1 blockade. These tumors exhibit high tumor mutational burden and a unique UV-induced signature, suggesting a distinct subgroup responsive to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Undifferentiated pleomorphic sarcoma (UPS) is an aggressive adult soft-tissue sarcoma.
- UPS is typically characterized by low tumor mutational burden (TMB) and high copy number alterations.
- Efficacy of programmed death-1 (PD-1) blockade in UPS has shown variable results.
Observation:
- Two patients with recurrent scalp UPS experienced clinical benefit from PD-1 blockade.
- These responsive UPS tumors exhibited high TMB with a UV-induced mutational pattern.
- Further analysis revealed five of seven head and neck UPS cases also had high TMB and a UV mutational signature.
Findings:
- Head and neck UPS tumors demonstrated increased programmed death-ligand 1 (PD-L1) expression.
- These tumors also showed higher CD8+ T-cell infiltration compared to UPS from other sites.
- Head and neck UPS presents a PD-L1 positive, T-cell-inflamed tumor microenvironment with high TMB.
Implications:
- Head and neck UPS may represent a distinct genetic subgroup of UPS.
- This subgroup's characteristics suggest potential efficacy of immune checkpoint inhibitor therapy.
- Findings support further investigation into PD-1 blockade for head and neck UPS.
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