Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures.

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.
Competing Interests: Competing interests: LC is employed by Janssen Research and Development at the time of this submission. LAD is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. He is a paid consultant to PGDx, 4Paws (PetDx), Innovatus CP and Neophore. He is an uncompensated consultant for Merck but has received research support for clinical trials from Merck. LAD is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD. He holds equity in PGDx, Jounce Therapeutics, Thrive Earlier Detection and Neophore. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. EJL has received institutional research grant funding from Bristol-Myers Squibb, Merck, and Regeneron. EJL is a consultant for Array BioPharma, Bristol-Myers Squibb, EMD Serono, MacroGenics, Novartis, Merck, Regeneron, Sanofi Genzyme. JMT serves on advisory boards for BMS, Merck, Akoya Biosciences, Astra Zeneca and has received research funding from BMS, Akoya Biosciences. RAA serves on advisory boards for Merck, Bristol Myers Squibb and FLX bio and has received research funding from Merck, Bristol Myers Squibb, and FLX bio. DMP serves on advisory boards for Merck, Bristol Myers Squibb and Compugen and has received research funding from Bristol Myers Squibb and Compugen. DTL serves on advisory boards for Merck and Bristol Myers Squibb and has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom. She has received speaking honoraria from Merck and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. The terms of these arrangements are being managed by Johns Hopkins. CFM was a paid consultant for Bayer and has received speakers bureau honoraria from Novartis. NJL has received funding support from Bristol Myers Squibb.
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