Radium-223 decreases PD-L1 expression in bone metastases: A study with [89Zr]Zr-atezolizumab PET and immunohistological correlation

Abstract Purpose Most patients with metastatic castration-resistant prostate cancer (mCRPC) do not benefit from treatment with immune checkpoint inhibitors targeting programmed cell death (ligand) 1 (PD-(L)1). Radiation might improve response to immunotherapy by increasing the immunogenicity of prostate cancer. The objective of this study was to investigate radium-223-mediated changes in the micro- and macroenvironment of mCRPC. Methods In this prospective, multicenter study (ICTRP NL-OMON26890), 28 patients with mCRPC and predominantly bone metastases were treated with radium-223, according to standard-of-care. Primary endpoint was failure-free survival (FFS). Imaging included sequential positron emission tomography (PET) with gallium-68 prostate-specific membrane antigen ( 68 Ga-PSMA) and zirconium-89 atezolizumab ( 89 Zr-atezolizumab) to quantify whole-body expression of PD-L1 in vivo (SUV mean/max ). Paired PET analysis included nine patients. The immune status of patients was characterized in biopsies from bone metastases and in blood using (multiplex) immunohistochemistry (IHC) and flow cytometry, respectively. Sequential biopsy analysis included two patients. Results 89 Zr-atezolizumab uptake in 68 Ga-PSMA positive bone metastases showed high intra- and inter-patient heterogeneity. In the total volume of 68 Ga-PSMA-positive bone lesions, the median SUV mean of 89 Zr-atezolizumab was 2.5 (IQR 0.9–3.4) at baseline and 0.9 (IQR 0.5–2.5) after three cycles of radium-223, which was higher than the physiological uptake in bone marrow at baseline and after treatment with radium-223. After three cycles of radium-223, 89 Zr-atezolizumab uptake decreased in bone metastases, independent of response on 68 Ga-PSMA PET, and the number of lymphocytes in tumor tissue and blood decreased concomitantly. Conclusions Treatment of mCRPC bone metastases with radium-223 results in a significant decrease of in vivo PD-L1-expression on PET imaging and a decrease in immune cells in bone metastases and blood. These findings indicate that treatment with alpha emitting radium-223 alters the immune microenvironment, thereby potentially reducing the efficacy of PD-(L)1 inhibitors.