High infiltration of CD209+ dendritic cells and CD163+ macrophages in the peritumor area of prostate cancer is predictive of late adverse outcomes

IntroductionProstate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions.MethodsInfiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves.ResultsPositive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209+ and CD163+ cells were more abundant at the tumor margin. Higher CD209+/CD83+ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163+ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively.ConclusionA higher level of infiltration of CD209+ immature DC and CD163+ M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes

La voie de signalisation PATCHED/Sonic Hedgehog dans le cancer superficiel de la vessie

Le cancer de la vessie se présente sous deux formes différentes: la forme superficielle et la forme infiltrante. La forme superficielle se caractérise par une fréquence élevée de pertes (totales ou partielles) du chromosome 9, notamment du bras long. Ces observations suggèrent la présence de gènes suppresseurs de tumeur (GST) dans cette région. Nous présentons le gène PATCHED, localisé en position 9q22.3, déjà impliqué dans le carcinome basocellulaire de la peau, comme un GST potentiel dans le cancer superficiel de la vessie.Superficial bladder cancer shows a high frequency of total or partial chromosome 9 losses. Loss of heterozygosity at position 9q22.3 is one of the most frequent and is associated with highly recurrent tumours. The PATCHED gene, ortholog of a gene first described in the drosophila as a segment polarity gene, is located at 9q22.3. It is a member of a signal transduction pathway and a tumour suppressor gene (TSG), involved in basal cell carcinoma. We propose PATCHED as a TSG candidate in superficial bladder cancer

Leukocytic Infiltration of Intraductal Carcinoma of the Prostate: An Exploratory Study

Intraductal carcinoma of the prostate (IDC-P) is an aggressive histological subtype of prostate cancer (PCa) detected in approximately 20% of radical prostatectomy (RP) specimens. As IDC-P has been associated with PCa-related death and poor responses to standard treatment, the purpose of this study was to explore the immune infiltrate of IDC-P. Hematoxylin- and eosin-stained slides from 96 patients with locally advanced PCa who underwent RP were reviewed to identify IDC-P. Immunohistochemical staining of CD3, CD8, CD45RO, FoxP3, CD68, CD163, CD209 and CD83 was performed. For each slide, the number of positive cells per mm2 in the benign tissues, tumor margins, cancer and IDC-P was calculated. Consequently, IDC-P was found in a total of 33 patients (34%). Overall, the immune infiltrate was similar in the IDC-P-positive and the IDC-P-negative patients. However, FoxP3+ regulatory T cells (p + and CD163+ macrophages (p + and CD83+ dendritic cells (p = 0.002 and p = 0.013, respectively) were less abundant in the IDC-P tissues compared to the adjacent PCa. Moreover, the patients were classified as having immunologically “cold” or “hot” IDC-P, according to the immune-cell densities averaged in the total IDC-P or in the immune hotspots. The CD68/CD163/CD209-immune hotspots predicted metastatic dissemination (p = 0.014) and PCa-related death (p = 0.009) in a Kaplan–Meier survival analysis. Further studies on larger cohorts are necessary to evaluate the clinical utility of assessing the immune infiltrate of IDC-P with regards to patient prognosis and the use of immunotherapy for lethal PCa

Identification of Morphologic Criteria Associated with Biochemical Recurrence in Intraductal Carcinoma of the Prostate

Intraductal carcinoma of the prostate (IDC-P) is an aggressive subtype of prostate cancer strongly associated with an increased risk of biochemical recurrence (BCR). However, approximately 40% of men with IDC-P remain BCR-free five years after radical prostatectomy. In this retrospective multicenter study, we aimed to identify histologic criteria associated with BCR for IDC-P lesions. A total of 108 first-line radical prostatectomy specimens were reviewed. In our test cohort (n = 39), presence of larger duct size (>573 µm in diameter), cells with irregular nuclear contours (CINC) (≥5 CINC in two distinct high-power fields), high mitotic score (>1.81 mitoses/mm2), blood vessels, and comedonecrosis were associated with early BCR (p n = 69), the presence of CINC or blood vessels was independently associated with an increased risk of BCR (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.09–4.96, p = 0.029). When combining the criteria, the presence of any CINC, blood vessels, high mitotic score, or comedonecrosis showed a stronger association with BCR (HR 2.74, 95% CI 1.21–6.19, p = 0.015). Our results suggest that IDC-P can be classified as low versus high-risk of BCR. The defined morphologic criteria can be easily assessed and should be integrated for clinical application following validation in larger cohorts

Immune-focused multi-omics analysis of prostate cancer: leukocyte Ig-Like receptors are associated with disease progression

International audienceProstate cancer (PCa) immunotherapy has shown limited efficacy so far, even in advanced-stage cancers. The success rate of PCa immunotherapy might be improved by approaches more adapted to the immunobiology of the disease. The objective of this study was to perform a multi-omics analysis to identify immune genes associated with PCa progression to better characterize PCa immunobiology and propose new immunotherapeutic targets. mRNA, miRNA, methylation, copy number aberration, and single nucleotide variant datasets from The Cancer Genome Atlas PRAD cohort were analyzed after filtering for genes associated with immunity. Sparse partial least squares-discriminant analyses were performed to identify features associated with biochemical recurrence (BCR) in each type of omics data. Selected features predicted BCR with a balanced error rate (BER) of 0.20 to 0.51 in single-omics and of 0.05 in multi-omics analyses. Amongst features associated with BCR were genes from the Immunoglobulin Ig-like Receptor (LILR) family which are immune checkpoints with immunotherapeutic potential. Using Multivariate INTegrative (MINT) analysis, the association of five LILR genes with BCR was quantified in a combination of three RNA-seq datasets and confirmed with Kaplan-Meier analysis in both these and in an independent RNA-seq dataset. Finally, immunohistochemistry showed that a high number of LILRB1 positive cells within the tumors predicted long-term adverse outcomes. Thus, tumors characterized by abnormal expression of LILR genes have an elevated risk of recurring after definitive local therapy. The immunotherapeutic potential of these regulators to stimulate the immune response against PCa should be evaluated in pre-clinical models

Factors affecting interindividual variability of hepatic UGT2B17 protein expression examined using a novel specific monoclonal antibody

The accurate quantification of the metabolic enzyme UGT2B17 has been hampered by the high sequence identity with other UGT2B enzymes (as high as 94%) and by the lack of a specific antibody. Knowing the significance of the UGT2B17 pathway in drug and hormone metabolism and cancer, we developed a specific monoclonal antibody (EL-2B17mAb), initially validated by the lack of detection in liver microsomes of an individual carrying no UGT2B17 gene copy and in supersomes expressing UGT2B enzymes. Immunohistochemical detection in livers reveals a strong labeling of bile ducts and variable labeling of hepatocytes. Expression levels assessed by immunoblotting were highly correlated to mass spectrometry-based quantification (r = 0.93) and three major expression patterns (absent, low or high) were evidenced. Livers with very low expression were carriers of the functional rs59678213 G variant, which is located in the binding site for the transcription factor Forkhead Box A1 (FOXA1) of the UGT2B17 promoter. The highest expression was observed for individuals carrying at least one rs59678213 A allele. A multiple regression analysis indicated that the number of gene copies explained only 8% of UGT2B17 protein expression, 49% when adding rs59678213 and reached 54% when including sex. The novel EL-2B17mAb antibody allowed specific UGT2B17 quantification and exposed different patterns of hepatic expression. It further suggests that FOXA1 is a key driver of UGT2B17 expression in the liver. The availability of this molecular tool will help characterize UGT2B17 level in various disease states and establish more precisely the UGT2B17 enzyme contribution to drug and hormone metabolis

Retrospective study on the benefit of adjuvant radiotherapy in men with intraductal carcinoma of prostate

Abstract Background Intraductal carcinoma of the prostate (IDC-P) is an independent biomarker of recurrence and survival with particular treatment response, yet no study has tested its response to radiotherapy. The aim of our project was to test the impact of adjuvant radiotherapy (ART) in patients with localized to locally advanced prostate cancer (PC) and IDC-P. Materials and methods We performed a retrospective study of men with pT2-T3 PC treated by radical prostatectomy (RP) with or without ART, from two centres (1993–2015). Exclusion criteria were the use of another type of treatment prior to biochemical recurrence (BCR), and detectable prostate- specific antigen (PSA) following RP or ART. Primary outcome was BCR (2 consecutive PSA ≥ 0.2 ng/ml). Patients were grouped by treatment (RPonly/RP + ART), IDC-P status, and presence of high-risk features (HRF: Grade Groups 4–5, positive margins, pT3 stage). Results We reviewed 293 RP specimens (median follow-up 99 months, 69 BCR). Forty-eight patients (16.4%) were treated by RP + ART. Multivariate Cox regression for BCR indicated that IDC-P had the strongest impact (hazard ratio [HR] = 2.39, 95% confidence interval [CI]:1.44–3.97), while ART reduced the risk of BCR (HR = 0.38, 95%CI: 0.17–0.85). Other HRF were all significant except for pT3b stage. IDC-P[+] patients who did not receive ART had the worst BCR-free survival (log-rank P = 0.023). Furthermore, IDC-P had the same impact on BCR-free survival as ≥1 HRF (log-rank P = 0.955). Conclusion Men with IDC-P who did not receive ART had the highest BCR rates, and IDC-P had the same impact as ≥1 HRF, which are often used as ART indications. Once validated, ART should be considered in patients with IDC-P

Uridine Diphosphate Glucuronosyl Transferase 2B28 (UGT2B28) Promotes Tumor Progression and Is Elevated in African American Prostate Cancer Patients

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa. UGT2B28 was found to be regulated by both full-length androgen receptor (AR) and its splice variant, AR-v7. Genetic knockdown of UGT2B28 across multiple PCa cell lines (LNCaP, LAPC-4, and VCaP), both in androgen-replete and androgen-depleted states resulted in impaired 3D organoid formation and a significant delay in tumor take and growth rate of xenograft tumors, all of which were rescued by re-expression of UGT2B28. Taken together, our findings demonstrate a key role for the UGT2B28 gene in promoting prostate tumor growth