A Novel PD-L1 Antibody Promotes Antitumor Function of Peripheral Cytotoxic Lymphocytes after Radical Nephrectomy in Patients with Renal Cell Carcinoma.

Autor:	An Z; Department of Immunology, Mayo Clinic, Rochester, MN.; Department of Urology, Mayo Clinic, Rochester, MN., Hsu MA; Department of Immunology, Mayo Clinic, Rochester, MN., Gicobi JK; Department of Immunology, Mayo Clinic, Rochester, MN., Xu T; Department of Immunology, Mayo Clinic, Rochester, MN., Harrington SM; Department of Urology, Mayo Clinic, Rochester, MN., Zhang H; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN., Pavelko KD; Immune Monitoring Core, Mayo Clinic, Rochester, MN., Hirdler JB; Department of Immunology, Mayo Clinic, Rochester, MN., Lohse CM; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN., Nabavizadeh R; Department of Urology, Mayo Clinic, Rochester, MN., Pessoa RR; Department of Urology, Mayo Clinic, Rochester, MN., Sharma V; Department of Urology, Mayo Clinic, Rochester, MN., Thompson RH; Department of Urology, Mayo Clinic, Rochester, MN., Leibovich BC; Department of Urology, Mayo Clinic, Rochester, MN., Dong H; Department of Immunology, Mayo Clinic, Rochester, MN.; Department of Urology, Mayo Clinic, Rochester, MN., Lucien F; Department of Immunology, Mayo Clinic, Rochester, MN.; Department of Urology, Mayo Clinic, Rochester, MN.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2023 Jun 15; Vol. 210 (12), pp. 2029-2037.
DOI:	10.4049/jimmunol.2200933
Abstrakt:	The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as "cytotoxic lymphocytes," or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma. (Copyright © 2023 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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