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Soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy in patients with metastatic clear cell renal cell carcinoma.

ABSTRACT: Metastatic clear cell renal cell carcinoma (mccRCC) benefits from several treatment options in the first-line setting with VEGFR inhibitors and/or immunotherapy including anti-PD-L1 or anti-PD1 agents. Identification of predictive biomarkers is highly needed to optimize patient care. Circulating markers could reflect the biology of metastatic disease. Therefore, we evaluated soluble forms of PD-L1 (sPD-L1) and PD-1 (sPD-1) in mccRCC patients. The levels of sPD-L1 and sPD-1 were evaluated from plasma samples of mccRCC patients before they received a first-line treatment (T0) by the VEGFR inhibitor sunitinib (50 patients) or by the anti-VEGF bevacizumab (37 patients). The levels of sPD-L1 and sPD-1 were correlated to clinical parameters and progression-free survival (PFS). High levels of sPD-1 or sPDL1 were not correlated to PFS under bevacizumab while they were independent prognostic factors of PFS in the sunitinib group. Patients with high T0 plasmatic levels of sPD-L1 had a shorter PFS (11.3 vs 22.5 months, p = .011) in the sunitinib group. Equivalent shorter PFS was found with high levels of sPD-1 (8.6 vs 14.1 months, p = .009). mccRCC patients with high plasmatic levels of sPD-L1 or sPD-1 are poor responders to sunitinib. sPD-L1 or sPD-1 could be a valuable tool to guide the optimal treatment strategy including VEGFR inhibitor.

SUBMITTER: Montemagno C

PROVIDER: S-EPMC7714499 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia.

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Soluble forms of PD-L1 and PD-1 as prognostic and predictive markers of sunitinib efficacy in patients with metastatic clear cell renal cell carcinoma.

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