Inhibition of PI3K pathway increases immune infiltrate in muscle-invasive bladder cancer.

Although immune checkpoint inhibitors have shown improvement in survival in comparison to chemotherapy in urothelial bladder cancer, many patients still fail to respond to these treatments and actual efforts are made to identify predictive factors of response to immunotherapy. Understanding the tumor-intrinsic molecular basis, like oncogenic pathways conditioning the presence or absence of tumor-infiltrating T cells (TILs), should provide a new rationale for improved anti-tumor immune therapies. In this study, we found that urothelial bladder cancer from human samples bearing PIK3CA gene mutations was significantly associated with lower expression of a defined immune gene signature, compared to unmutated ones. We identified a reduced 10-gene immune gene signature that discriminates muscle-invasive bladder cancer (MIBC) samples according to immune infiltration and PIK3CA mutation. Using a humanized mouse model, we observed that BKM120, a pan-PI3K inhibitor, significantly inhibited the growth of a human bladder cancer cell line bearing a PIK3CA mutation, associated to increased immune cell infiltration (hCD45+). Using qRT-PCR, we also found an increase in the expression of chemokines and immune genes in PIK3CA-mutated tumors from mice treated with BKM120, reflecting an active immune infiltrate in comparison to untreated ones. Moreover, the addition of BKM120 rendered PIK3CA-mutated tumors sensitive to PD-1 blockade. Our results provide a relevant rationale for combination strategies of PI3K inhibitors with immune checkpoint inhibitors to overcome resistance to immune checkpoint inhibitors.

Precision Matters in MR Imaging-targeted Prostate Biopsies: Evidence from a Prospective Study of Cognitive and Elastic Fusion Registration Transrectal Biopsies.

Purpose To measure the precision in placement of a biopsy needle in a magnetic resonance (MR) imaging-detected target with transrectal ultrasonography (US), to document the clinical relevance of precision, and to report on the precision of cognitive and software-based registrations. Materials and Methods This prospective study was approved by the institutional review board and performed between June 2013 and September 2013. Patients provided informed verbal consent. Two cores each were obtained with cognitive and fusion techniques in 88 patients with a Prostate Imaging Reporting and Data System version 1 score of at least 3. Precision was measured with Euclidian geometry by using the Digital Imaging and Communications in Medicine archives of the biopsy as the distance from the core to the center (dCC) and the distance from the core to the surface of the target modeled as a sphere. To address clustering of data from multiple cores in the same patients, analyses of precision focused on the best shot for a patient or a technique. The Welch unequal variance t test and Yates corrected χ2 test were used as appropriate. Results Mean precision was 2.5 mm (95% confidence interval: 1.8 mm, 3.3 mm). Positive cores were closer to the center than were negative cores (dCC: 1.7 mm vs 3.1 mm, respectively; P = .025). More cancers were detected with on-target than off-target cores (33 of 71 cores [46.5%] vs three of 17 cores [17.6%]; P = .03). Cores obtained with the fusion technique achieved a higher precision than did cores obtained with the cognitive technique (dCC: 2.8 mm vs 7.1 mm, respectively; P < .0001). Targeted cores demonstrated cancer in 44 patients. Fewer cancers were detected with the cognitive technique than with the fusion technique (31 of 44 patients [70.5%] vs 40 of 44 patients [90.9%]; P = .03). Conclusion A deformable MR imaging/transrectal US image registration system achieved a higher precision and depicted cancer in more patients than did the cognitive freehand technique. © RSNA, 2018.

HIV-1 efficient entry in inner foreskin is mediated by elevated CCL5/RANTES that recruits T cells and fuels conjugate formation with Langerhans cells.

Male circumcision reduces acquisition of HIV-1 by 60%. Hence, the foreskin is an HIV-1 entry portal during sexual transmission. We recently reported that efficient HIV-1 transmission occurs following 1 h of polarized exposure of the inner, but not outer, foreskin to HIV-1-infected cells, but not to cell-free virus. At this early time point, Langerhans cells (LCs) and T-cells within the inner foreskin epidermis are the first cells targeted by the virus. To gain in-depth insight into the molecular mechanisms governing inner foreskin HIV-1 entry, foreskin explants were inoculated with HIV-1-infeceted cells for 4 h. The chemokine/cytokine milieu secreted by the foreskin tissue, and resulting modifications in density and spatial distribution of T-cells and LCs, were then investigated. Our studies show that in the inner foreskin, inoculation with HIV-1-infected cells induces increased CCL5/RANTES (1.63-fold) and decreased CCL20/MIP-3-alpha (0.62-fold) secretion. Elevated CCL5/RANTES mediates recruitment of T-cells from the dermis into the epidermis, which is blocked by a neutralizing CCL5/RANTES Ab. In parallel, HIV-1-infected cells mediate a bi-phasic modification in the spatial distribution of epidermal LCs: attraction to the apical surface at 1 h, followed by migration back towards the basement membrane later on at 4 h, in correlation with reduced CCL20/MIP-3-alpha at this time point. T-cell recruitment fuels the continuous formation of LC-T-cell conjugates, permitting the transfer of HIV-1 captured by LCs. Together, these results reveal that HIV-1 induces a dynamic process of immune cells relocation in the inner foreskin that is associated with specific chemokines secretion, which favors efficient HIV-1 entry at this site.