GRPR versus PSMA:expression profiles during prostate cancer progression demonstrate the added value of GRPR-targeting theranostic approaches

Introduction: Central to targeted radionuclide imaging and therapy of prostate cancer (PCa) are prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals. Gastrin-releasing peptide receptor (GRPR) targeting has been proposed as a potential additional approach for PCa theranostics. The aim of this study was to investigate to what extent and at what stage of the disease GRPR-targeting applications can complement PSMA-targeting theranostics in the management of PCa. Methods: Binding of the GRPR- and PSMA-targeting radiopharmaceuticals [177Lu]Lu-NeoB and [177Lu]Lu-PSMA-617, respectively, was evaluated and compared on tissue sections of 20 benign prostatic hyperplasia (BPH), 16 primary PCa and 17 progressive castration-resistant PCa (CRPC) fresh frozen tissue specimens. Hematoxylin-eosin and alpha-methylacyl-CoA racemase stains were performed to identify regions of prostatic adenocarcinoma and potentially high-grade prostatic intraepithelial neoplasia. For a subset of primary PCa samples, RNA in situ hybridization (ISH) was used to identify target mRNA expression in defined tumor regions. Results: The highest median [177Lu]Lu-NeoB binding was observed in primary PCa samples, while median and overall [177Lu]Lu-PSMA-617 binding was highest in CRPC samples. The highest [177Lu]Lu-NeoB binding was observed in 3/17 CRPC samples of which one sample showed no [177Lu]Lu-PSMA-617 binding. RNA ISH analyses showed a trend between mRNA expression and radiopharmaceutical binding, and confirmed the distinct GRPR and PSMA expression patterns in primary PCa observed with radiopharmaceutical binding. Conclusion: Our study emphasizes that GRPR-targeting approaches can contribute to improved PCa management and complement currently applied PSMA-targeting strategies in both early and late stage PCa.</p

Intratumoral Niches of B Cells and Follicular Helper T Cells, and the Absence of Regulatory T Cells, Associate with Longer Survival in Early-Stage Oral Tongue Cancer Patients

Simple Summary The 5-year survival of patients with early-stage oral cancer remains at 80% despite advances in treatment. We have previously shown that the proximity between CD20 B cells and CD4 T cells in the invasive margin acts as an independent prognosticator in OSCC, represented by the so-called CD20 cluster score. However, its exact underlying cellular contexture is unknown. In this study, we demonstrated that the abundance of follicular helper T cells as well as the proximity between these cells and B cells were important hallmarks for patients with a high CD20 cluster score and long survival. In early oral squamous cell carcinoma (OSCC), the occurrence of clusters between CD20 B cells and CD4 T cells in the invasive margin (IM) can be captured by using the CD20 cluster score, and is positively associated with patient survival. However, the exact contribution of different CD4 T cell subsets, as well as B cell subsets toward patient prognosis is largely unknown. To this end, we studied regulatory T cells ((Treg cells) FOXP3 and CD4), T helper-type 1 cells ((Th1 cells) Tbet and CD4), follicular helper T cells ((Tfh cells) Bcl6 and CD4), B cells (CD20), germinal center B cells ((GC B cells) BCL6 and CD20), and follicular dendritic cells ((fDCs) CD21) for their density, location, and interspacing using multiplex in situ immunofluorescence of 75 treatment-naive, primary OSCC patients. We observed that Treg, Th1-, Tfh-, and GC B cells, but not fDCs, were abundantly present in the stroma as compared with the tumor, and in the IM as compared with in the center of the tumor. Patients with high CD20 cluster scores had a high density of all three CD4 T cell subsets and GC B cells in the stromal IM as compared with patients with low CD20 cluster scores. Notably, enriched abundance of Tfh cells (HR 0.20, p = 0.04), and diminished abundance of Treg cells (HR 0.10, p = 0.03), together with an overall short distance between Tfh and B cells (HR:0.08, p < 0.01), but not between Treg and B cells (HR 0.43, p = 0.28), were significantly associated with overall survival of patients with OSCC. Our study identified the prognostic value of clusters between CD20 B cells and Tfh cells in the stromal IM of OSCC patients, and enabled an improved understanding of the clinical value of a high CD20 cluster score, which requires validation in larger clinical cohorts