Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas

Abstract

Soft tissue sarcomas (STS) are highly malignant cancers with mesenchymal origin. In many instances, clinical outcome is poor due to high rates of local recurrence and metastasis.\n\nThe programmed death receptor ligand 1 (PD-L1) is expressed in several cancers. PD-L1 interacts with its receptor, PD-1, on the surface of tumor infiltrating lymphocytes (TILs), thereby attenuating anti-cancer immune response. Immune checkpoint inhibitors targeting this interaction are promising new anti-cancer drugs. However, present studies on the PD-L1 and PD-1 expression status in STS are limited either by small sample size, analysis of single STS subtypes, or lack of combinatorial assessment of PD-L1, PD-1 and TILs.\n\nTo overcome these limitations, we evaluated the expression patterns of intratumoral PD-L1, the amount of TILs and their PD-1 expression status, as well as associations with clinicopathological parameters in a large and comprehensive cohort of 274 samples comprising more than six STS subtypes.\n\nWe found that nearly all STS subtypes showed partial PD-L1 expression, albeit with a broad range of PD-L1 positivity across subtypes (50% angiosarcomas, 23% UPS, 13% leiomyosarcomas, 12% dedifferentiated liposarcomas, 3% synovial sarcomas, 0 MPNST, and 18% mixed sarcomas). Co-expression and correlation analyses uncovered that expression of PD-L1 was associated with more PD-1 positive TILs (P < 0.001), higher tumor grading (P = 0.022) and worse patients 5-year overall survival (P = 0.016).\n\nIn sum, the substantial portion of STS showing PD-L1 expression, the simultaneous presence of PD-1 positive TILs, and the association of PD-L1 with unfavorable clinical outcome provide a rationale for immune checkpoint inhibition in patients with PD-L1-positive STS.