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

Abstract

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. 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 (⁶⁸Ga-PSMA) and zirconium-89 atezolizumab (⁸⁹Zr-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. ⁸⁹Zr-atezolizumab uptake in ⁶⁸Ga-PSMA positive bone metastases showed high intra- and inter-patient heterogeneity. In the total volume of ⁶⁸Ga-PSMA-positive bone lesions, the median SUV_mean of ⁸⁹Zr-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, ⁸⁹Zr-atezolizumab uptake decreased in bone metastases, independent of response on ⁶⁸Ga-PSMA PET, and the number of lymphocytes in tumor tissue and blood decreased concomitantly. 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. 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). By increasing the immunogenicity of the immunosuppressive prostate cancer microenvironment, radiation might improve response to immunotherapy. Therefore, we aimed to gain insight into the immune response to the radionuclide radium-223. In this prospective study, 28 patients with mCRPC were treated with radium-223. Using positron emission tomography (PET) with gallium-68 prostate-specific membrane antigen (68Ga-PSMA) and zirconium-89 atezolizumab (⁸⁹Zr-atezolizumab), we showed that whole-body expression of PD-L1 decreased after treatment with radium-223. In addition, the number of lymphocytes in tumor tissue and blood decreased. These findings indicate that treatment with alpha emitting radium-223 negatively affects the immune microenvironment, thereby impeding treatment with PD-(L)1 inhibitors.