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

By Martin F. Orth, Veit L. Buecklein, Eric Kampmann, Marion Subklewe, Elfriede Noessner, Florencia Cidre-Aranaz, Laura Romero-Pérez, Fabienne S. Wehweck, Lars Lindner, Rolf Issels, Thomas Kirchner, Annelore Altendorf-Hofmann, Thomas G. P. Grünewald, Thomas Knösel

Posted 08 Mar 2019
bioRxiv DOI: 10.1101/569418

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. The 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. To 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. We 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). In 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.

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