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

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.

Prevalence of PD-L1 expression in matched recurrent and/or metastatic sarcoma samples and in a range of selected sarcomas subtypes

“…This would make comparative analyses reliable. Although radiotherapy has been shown to induce PD-L1 expression [33], our cases with documented post-radiotherapy (Table 1; n = 5) showed <10% PD-L1 expression. Finally, the size of the metastatic/recurrent cohort is limited and therefore, a larger number of paired samples is needed to further validate these findings.…”

“…For instance, PD-L1 can be constitutive or inducible in response to IFN-γ released by effector T cells. Inducible PD-L1 can be affected by tumour location and prior therapy (Reviewed in [1]) including radiotherapy [33]. At the current time, there is not enough literature to address the dynamics of inducible PD-L1, as a result of therapy but if such changes occur, these may potentially provide therapeutic avenues to patients who may not initially be suitable for anti-PD-L1 therapy.…”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…Early studies have demonstrated that immunotherapy and radiation can safely be administered together and may induce responses, but questions remain regarding the optimal timing of systemic treatment with radiation, radiation dose, and tumour volume irradiated . Recent work in human sarcomas has suggested that radiation upregulates common targets of recently approved immune checkpoint inhibitors such as PD‐L1 . While immune checkpoint inhibitors have been approved for use in advanced disease settings or in conjunction with chemotherapy, none are approved for use with RT, and the mechanism for synergy remains incompletely understood .…”

“…Cancer cells learn to evade the immune system by exploiting immune checkpoint pathways that prevent T lymphocytes from recognizing tumour-specific antigens. 124,125 There has been a recent change in clinical practice to incorporate immune checkpoint inhibitors into the management of a wide variety of advanced tumours, including melanoma, nonsmall cell lung cancer, lymphoma, head and neck tumours, gastrointestinal tumours, and genitourinary tumours. 60,126,127 Their use can also be extended to soft tissue sarcoma and osteosarcoma.…”

“…60,126,163 Recent work in human sarcomas has suggested that radiation upregulates common targets of recently approved immune checkpoint inhibitors such as PD-L1. 125,163,164 While immune checkpoint inhibitors have been approved for use in advanced disease settings or in conjunction with chemotherapy, none are approved for use with RT, and the mechanism for synergy remains incompletely understood. 126 Initial trials combining RT with checkpoint blockade have been performed in the treatment-refractory metastatic setting and recruitment of sarcomas has been poor.…”