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A comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas

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Abstract

Soft tissue sarcomas (STSs) are heterogeneous cancers associated with poor prognosis 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 have been established as effective anti-cancer drugs. However, studies on the PD-L1 and PD-1 expression status in STS are commonly limited by small sample size, analysis of single STS subtypes, or lack of combinatorial marker assessment. To overcome these limitations, we evaluated the expression patterns of intratumoral PD-L1, the number of TILs, their PD-1 expression, and associations with clinicopathological parameters in a large and comprehensive cohort of 225 samples comprising six STS subtypes. We found that nearly all STS subtypes showed PD-L1 expression on the tumor cells, albeit with a broad range of positivity across subtypes (50% angiosarcomas to 3% synovial sarcomas). Co-expression and correlation analyses uncovered that PD-L1 expression was associated with more PD-1-positive TILs (P < 0.001), higher tumor grading (P = 0.016), and worse patients’ 5-year overall survival (P = 0.028). The results were in line with several publications on single STS subtypes, especially when comparing findings for STS with low and high mutational burden. In sum, the substantial portion of PD-L1 positivity, the co-occurrence of PD-1-positive TILs, and the association of PD-L1 with unfavorable clinical outcome provide rationales for immune checkpoint inhibition in patients with PD-L1-positive STS.

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Abbreviations

GIST:

Gastrointestinal stromal tumor

HPF:

High-power field

IHC:

Immunohistochemistry

MPNST:

Malignant peripheral nerve sheath tumor

STS:

Soft tissue sarcoma

TIL:

Tumor-infiltrating lymphocyte

TMA:

Tissue microarray

UPS:

Undifferentiated pleomorphic sarcoma

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Acknowledgements

We thank A. Heier, M. Melz, A. Sendelhofert, and S. Stein for excellent technical support.

Funding

The laboratory of TGPG is supported by grants from the ‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Friedrich-Baur foundation, the Matthias-Lackas foundation, the Dr. Leopold und Carmen Ellinger foundation, the Barbara und Hubertus Trettner foundation, the Dr. Rolf M. Schwiete foundation, the Gert & Susanna Mayer foundation, the Deutsche Forschungsgemeinschaft (DFG 391665916), and by the German Cancer Aid (70112257). None of the funders had any influence on study design, data acquisition, interpretation, and paper writing.

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Author notes

  1. Thomas G. P. Grünewald and Thomas Knösel share senior authorship.

Authors and Affiliations

  1. Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians University Munich, Munich, Germany

    Martin F. Orth, Florencia Cidre-Aranaz, Laura Romero-Pérez, Fabienne Sophie Wehweck & Thomas G. P. Grünewald

  2. Department of Internal Medicine III, Faculty of Medicine, Ludwig-Maximilians University Munich, Munich, Germany

    Veit Leonhard Buecklein, Eric Kampmann, Marion Subklewe, Lars Lindner & Rolf Issels

  3. Institute of Molecular Immunology, Helmholtz Center, Munich, Germany

    Elfriede Noessner

  4. Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians University Munich, Thalkirchner Str. 36, 80337, Munich, Germany

    Fabienne Sophie Wehweck, Thomas Kirchner, Thomas G. P. Grünewald & Thomas Knösel

  5. German Cancer Consortium (DKTK), partner site Munich, Munich, Germany

    Thomas Kirchner & Thomas G. P. Grünewald

  6. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Thomas Kirchner & Thomas G. P. Grünewald

  7. Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University, Jena, Germany

    Annelore Altendorf-Hofmann

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Contributions

MFO analyzed the data, performed statistical analysis, and wrote the paper together with TGPG. EK and TKn scored the IHC staining of PD-L1 and PD-1. FCA, LRP, and FSW scored Ki-67 staining. VLB, MS, EN, LL, and RI supplied clinical data. AAH carried out statistical analyses. TGPG and TKi provided laboratory infrastructure. TKn conceived the project, drafted the paper, and supervised the analyses together with TGPG. All authors read and approved the final manuscript.

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Correspondence to Thomas G. P. Grünewald or Thomas Knösel.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committees of the LMU Munich University hospital (307-16 UE, 25.05.2016) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Orth, M.F., Buecklein, V.L., Kampmann, E. et al. A comparative view on the expression patterns of PD-L1 and PD-1 in soft tissue sarcomas. Cancer Immunol Immunother 69, 1353–1362 (2020). https://doi.org/10.1007/s00262-020-02552-5

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