The Prognostic Significance of Selected HLA Alleles on Prostate Cancer Outcome.

Recently, we have shown that HLA-A*02:01 and HLA-A*24:02 in de novo metastatic prostate cancer (MPCa) have an important role in disease progression. Since de novo MPCa represents a small group among patients diagnosed with prostate cancer (PCa), it was obvious to try to extend the validity of our results to larger cohorts of PCa patients. Herein, we analyzed patients irrespective of their disease status at diagnosis to include, besides patients with MPCa, those with localized PCa (LPCa). Our goal was to specify the prognostic value of HLA-A*02:01 and HLA-A*24:02 for overall survival (OS) prospectively and for early biochemical recurrence (BCR) and castrate resistance (CR) as additional clinical endpoints in a prospective/retrospective manner, to improve clinical decisions for patients covering all stages of PCa. On univariate analysis, HLA-A alleles were significantly associated as prognostic biomarkers with early BCR (p = 0.028; HR = 1.822), OS (p = 0.013; HR = 1.547) and showed a trend for CR (p = 0.150; HR = 1.239). On multivariate analysis, HLA-A alleles proved to be independent prognosticators for early BCR (p = 0.017; HR = 2.008), CR (p = 0.005; HR = 1.615), and OS (p = 0.002; HR = 2.063). Kaplan-Meier analyses revealed that patients belonging to the HLA-A*02:01+HLA-A*24:02- group progressed much faster to BCR and CR and had also shorter OS compared to HLA-A*24:02+ patients. Patients being HLA-A*02:01-HLA-A*24:02- exhibited varying clinical outcomes, pointing to the presence of additional HLA-A alleles with potential prognostic value. Our data underline the HLA-A alleles as valuable prognostic biomarkers for PCa that may assist with the appropriate treatment and follow-up schedule based on the risk for disease progression to avoid over-diagnosis and over-treatment.

Frequencies of an Immunogenic HER-2/neu Epitope of CD8+ T Lymphocytes Predict Favorable Clinical Outcomes in Prostate Cancer.

HER-2/neu is the human epidermal growth factor receptor 2, which is associated with the progression of prostate cancer (PCa). HER-2/neu-specific T cell immunity has been shown to predict immunologic and clinical responses in PCa patients treated with HER-2/neu peptide vaccines. However, its prognostic role in PCa patients receiving conventional treatment is unknown, and this was addressed in this study. The densities of CD8+ T cells specific for the HER-2/neu(780-788) peptide in the peripheral blood of PCa patients under standard treatments were correlated with TGF-ß/IL-8 levels and clinical outcomes. We demonstrated that PCa patients with high frequencies of HER-2/neu(780-788)-specific CD8+ T lymphocytes had better progression-free survival (PFS) as compared with PCa patients with low frequencies. Increased frequencies of HER-2/neu(780-788)-specific CD8+ T lymphocytes were also associated with lower levels of TGF-ß and IL-8. Our data provide the first evidence of the predictive role of HER-2/neu-specific T cell immunity in PCa.

A Blood-Based Immune Gene Signature with Prognostic Significance in Localized Prostate Cancer.

Prostate cancer (PCa) is one of the most common male cancers worldwide and one of the deadliest if unsuccessfully treated. Τhe need for reliable, easily accessible immune-related molecular biomarkers that could be combined with clinically defined criteria, including PSA and Gleason score, to accurately predict PCa patients' clinical outcomes is emerging. Herein, we describe for the first time a blood-identified immune-related gene signature comprising eight upregulated multi-functional genes associated with poor prognosis. Next-generation sequencing (NGS) analysis of PCa patients' peripheral blood samples revealed a more than three-fold upregulation of each of the eight genes as compared to samples originating from healthy donors. The construction of gene and protein interaction networks revealed different extents of the functional implications of these genes in the regulation of cell proliferation and immune responses. Analysis of the available data from The Cancer Genome Atlas (TCGA) regarding gene expression and survival of prostate adenocarcinoma (PRAD) and pan-cancer (PANCAN) patients revealed that intra-tumoral upregulation of this eight-gene signature (8-GS) was associated with poor 5-year progression-free intervals in PCa patients, even in those with high Gleason scores, and also with an unfavorable prognosis for cancer patients irrespective of the cancer type and even in the early stages. These observations suggest that further investigation of the 8-GS prospectively in randomized clinical trials, in which clinical benefit in terms of evaluating time to disease progression can be assessed, is warranted.

Correction: Kogionou et al. Radiotherapy-Related Gene Signature in Prostate Cancer. Cancers 2022, 14, 5032.

The authors wish to make the following corrections to this paper [...].

Radiotherapy-Related Gene Signature in Prostate Cancer.

Radiotherapy for localized prostate cancer has increased the cure and survival rates of patients. Besides its local tumoricidal effects, ionizing radiation has been linked to mechanisms leading to systemic immune activation, a phenomenon called the abscopal effect. In this study, we performed gene expression analysis on peripheral blood from prostate cancer patients obtained post- radiotherapy and showed that 6 genes, including CCR7, FCGR2B, BTLA, CD6, CD3D, and CD3E, were down-regulated by a range of 1.5-2.5-fold as compared to pre-radiotherapy samples. The expression of the signature consisting of these six genes was also significantly lower post- vs. pre-radiotherapy. These genes are involved in various tumor-promoting immune pathways and their down-regulation post-radiotherapy could be considered beneficial for patients. This is supported by the fact that low mRNA expression levels for the 6-gene signature in the prostate tumor tissue was linked to better survival. Importantly, we report that this 6-gene signature strongly correlated with a favorable prognosis regardless of poor standard clinicopathological parameters (i.e., Gleason score ≥ 8 and T3 (including T3a and T3b). Our pioneering data open the possibility that the 6-gene signature identified herein may have a predictive value, but this requires further long-term studies.

The impact of radiation therapy on the TCR Vß chain repertoire in patients with prostate cancer.

Radiation therapy (RT) is an essential component in the therapeutic treatment of patients with localized prostate cancer (LPCa). Besides its local effects, ionizing radiation has been linked to mechanisms leading to systemic immune activation. The present study explored the effect of RT on the T­cell receptor variable ß (TCR Vß) chain repertoire of peripheral blood T cells in patients with LPCa. High­throughput TCR Vß sequencing was performed on 20 blood samples collected from patients with LPCa at baseline and 3 months post­RT. The diversity index was altered, as were TCR Vß clonal evenness and convergence before and post­RT; however, these findings were not significant. Notably, marked changes in the frequencies among the top 10 TCR Vß clonotypes were detected and some patients developed new clonotypes of high abundance. These data provided initial evidence that RT in patients with LPCa may induce systemic immune changes, which could be exploited by future therapies for improved clinical results.

Identification of two novel alleles, HLA-A*02:01:193 and -DQA1*02:17, in Greek individuals.

Identification by NGS of two novel alleles, HLA-A*02:01:193 and -DQA1*02:17, in Greek individuals.

HLA Class I Allele Expression and Clinical Outcome in De Novo Metastatic Prostate Cancer.

The prognostic value of human leukocyte antigen (HLA) class I molecules in prostate cancer (PCa) remains unclear. Herein, we investigated the prognostic relevance of the most frequently expressed HLA-A alleles in Greece (A*02:01 and HLA-A*24:02) in de novo metastatic hormone-sensitive PCa (mPCa), which is a rare and aggressive disease characterized by a rapid progression to castration-resistance (CR) and poor overall survival (OS), contributing to almost 50% of PCa-related deaths. We identified 56 patients who had either progressed to CR (these patients were retrospectively analyzed for the time to the progression of CR and prospectively for OS) or had at least three months' follow-up postdiagnosis without CR progression and, thus, were prospectively analyzed for both CR and OS. Patients expressing HLA-A*02:01 showed poor clinical outcomes vs. HLA-A*02:01-negative patients. HLA-A*24:02-positive patients progressed slower to CR and had increased OS. Homozygous HLA-A*02:01 patients progressed severely to CR, with very short OS. Multivariate analyses ascribed to both HLA alleles significant prognostic values for the time to progression (TTP) to CR and OS. The presence of HLA-A*02:01 and HLA-A*24:02 alleles in de novo mPCa patients are significantly and independently associated with unfavorable or favorable clinical outcomes, respectively, suggesting their possible prognostic relevance for treatment decision-making in the context of precision medicine.