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. 2018 Mar 15;7(7):e1442168.
doi: 10.1080/2162402X.2018.1442168. eCollection 2018.

Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma

Kirtesh R Patel  1 , Anthony Martinez  2 , John M Stahl  1 , Suzanna J Logan  2 , Adam J Perricone  2 , Matthew J Ferris  3 , Zachary S Buchwald  3 , Mudit Chowdhary  3 , Keith A Delman  4 , David K Monson  5 , Shervin V Oskouei  5 , Nicholas B Reimer  5 , Kenneth Cardona  4 , Mark A Edgar  2 , Karen D Godette  3
Affiliations

Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma

Kirtesh R Patel et al. Oncoimmunology. .

Abstract

Soft tissue sarcomas (STS) have minimal expression of PD-L1, a biomarker for PD-1 therapy efficacy. Radiotherapy (RT) has been shown to increase PD-L1 expression pre-clinically. We examined the expression of PD-L1, pre- and post-RT, in 46 Stage II-III STS patients treated with pre-operative RT (50-50.4 Gy in 25-28 fractions) followed by resection. Five additional patients who did not receive RT were utilized as controls. PD-L1 expression on biopsy and resection samples was evaluated by immunochemistry using the anti PD-L1 monoclonal antibody (E1L3 N clone; Cell Signaling). Greater than 1% membranous staining was considered positive PD-L1 expression. Changes in PD-L1 expression were analyzed via the Fisher exact test. Kaplan-Meier statistics were used to correlate PD-L1 expression to distant metastases (DM) rate. The majority of STS were T2b (87.0%), high-grade (80.4%), undifferentiated pleomorphic histology (71.7%), and originated from the extremities (84.6%). Zero patients demonstrated PD-L1 tumor expression pre-RT. Post-RT, 5 patients (10.9%) demonstrated PD-L1 tumor expression (p = 0.056). Tumor associated macrophages (TAM) expression of PD-L1 increased after RT: 15.2% to 45.7% (p = 0.003). Samples from controls demonstrated no baseline (0%) or change in tumor PD-L1 expression. Freedom from DM was lower for patients with PD-L1 TAM expression post-RT (3 years: 49.7% vs. 87.8%, log-rank p = 0.006); TAM PD-L1 positivity remained an independent predictor for DM on multivariate analyses (Hazard ratio - 0.16, 95% confidence interval: 0.034-0.721, p = 0.042). PD-L1 expression on human STS tumor and TAM appears to elevate after pre-operative RT. Expression of PD-L1 on TAM after RT was associated with a higher rate of DM.

Keywords: Immunotherapy; PD-L1; Radiation; Soft Tissue Sarcoma.

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Figures

Figure 1.
Figure 1.
PD-L1 expression in undifferentiated pleomorphic sarcoma pre (A-D) and post (E-H) radiation therapy. Prior to radiation therapy, tumor cells and tumor associated macrophages are negative for PD-L1 (C-D). After radiation therapy, both tumor cells (straight arrows) and macrophages (curved arrows) are positive for PD-L1. A, C, E, G: 10x; B, D, F, H: 40x.
Figure 2.
Figure 2.
Comparing distant metastases free survival, via Kaplan-Meier plots, between sarcoma patients who express and do not express PD-L1 on macrophages after pre-operative radiation therapy.
See this image and copyright information in PMC

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