Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression

Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the proangiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing proangiogenic TIE2+, M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumorbearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME

The Microbiome of the Prostate Tumor Microenvironment

Background: The advent of molecular-based methods of identification and characterization of complex microbial populations has led to a new era of microbial discovery. A detailed and comprehensive analysis of the microbial ecosystem of the pathologic and healthy prostate tissues has not been yet reported. Objectives: To characterize the microbiome possibly associated to the pathologic prostate microenvironment. Design, setting, and participants: The microbiome profile of tumor, peri-tumor, and nontumor tissues was assessed on 16 radical prostatectomy-specimens. Outcome measurements and statistical analysis: Microbiome analysis was assessed by massive ultradeep pyrosequencing. Bacteria load was expressed as a percentage of the total number of bacteria. The statistical significance of differences among specimen-groups was tested with Friedman's test (Dunn posthoc test) and Wilcoxon rank-sum test. Results and limitations: Three phyla, six classes, nine orders, 14 families, and 11 genera were above the set threshold value of 1%, respectively. Significant differences in specific microbial populations among tumor/peri-tumor and nontumor prostate specimens were observed at certain taxonomic levels. Among genera, Propionibacterium spp. were the most abundant. Staphylococcus spp. were more represented in the tumor/peri-tumor tissues (p <. 0.05). The restricted number of specimens represents a potential limitation. Conclusions: The prostate contains a plethora of bacteria, which set themselves within the gland with a distribution dependent on the nature of the tissue, thus suggesting a possible pathophysiological correlation between the composition of the local microbial niche and the presence of the tumor itself. Future studies will help to clarify the role of these specific bacteria and their potential to be exploited as new biomarkers. Patient summary: The pathological prostate is populated by specific microbial populations, whose distribution varies according to the nature of the tissue. This finding opens interesting perspectives for the identification of novel therapeutic approaches and biomarkers. The prostate contains a plethora of bacteria, which set themselves within the gland with a distribution dependent on the nature of the tissue, suggesting a possible pathophysiological correlation between the specific local microbial niche and the tumor itself