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Follicular T cells provide help to B cells to elicit antibody responses. Cerutti and colleagues show that neutrophils provide help to marginal-zone B cells that produce T cell–independent antibodies. Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell–independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell–helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell–independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. This trend was validated in an additional cohort. Additionally, we found that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting that a high immune cell infiltration signature could be a better predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different signatures should be considered for predictive models.

We studied the non-obese diabetic (NOD) mice model because it develops autoimmune diabetes that resembles human type 1 diabetes. In diabetic mice, urinary albumin excretion (UAE) was ten-fold increased at an \"early stage\" of diabetes, and twenty-fold increased at a \"later stage\" (21 and 40 days, respectively after diabetes diagnosis) as compared to non-obese resistant controls. In NOD Diabetic mice, glomerular enlargement, increased glomerular filtration rate (GFR) and increased blood pressure were observed in the early stage. In the late stage, NOD Diabetic mice developed mesangial expansion and reduced podocyte number. Circulating and urine ACE2 activity were markedly increased both, early and late in Diabetic mice. Insulin administration prevented albuminuria, markedly reduced GFR, blood pressure, and glomerular enlargement in the early stage; and prevented mesangial expansion and the reduced podocyte number in the late stage of diabetes. The increase in serum and urine ACE2 activity was normalized by insulin administration at the early and late stages of diabetes in Diabetic mice. We conclude that the Diabetic mice develops features of early kidney disease, including albuminuria and a marked increase in GFR. ACE2 activity is increased starting at an early stage in both serum and urine. Moreover, these alterations can be completely prevented by the chronic administration of insulin.

Advanced prostate and bladder cancer are two outstanding unmet medical needs for urological oncologists. The high prevalence of these tumours, lack of effective biomarkers and limited effective treatment options highlight the importance of basic research in these diseases. Galectins are a family of β-galactoside-binding proteins that are frequently altered (upregulated or downregulated) in a wide range of tumours and have roles in different stages of tumour development and progression, including immune evasion. In particular, altered expression levels of different members of the galectin family have been reported in prostate and bladder cancers, which, together with the aberrant glycosylation patterns found in tumour cells and the constituent cell types of the tumour microenvironment, can result in malignant transformation and tumour progression. Understanding the roles of galectin family proteins in the development and progression of prostate and bladder cancer could yield key insights to inform the clinical management of these diseases.Galectins have established roles in cancer, but their function in genitourinary cancer is unclear. In this Opinion, the authors discuss the emerging roles of galectins in prostate and bladder cancer development and progression and speculate regarding opportunities for clinical translation.

Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI–mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs. Marginal zone B cells differentiate into plasma cells rapidly in response to T-cell-independent antigens, but how they do so is not clear. Here the authors show TACI cooperates with TLR signalling to drive mTOR activity and subsequent class switching and plasmablast differentiation.

Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, genetic, and epigenetic levels. Exome sequencing has identified ARID1A as a novel tumor suppressor gene coding for a chromatin remodeling protein that is mutated in UBC. Here, we assess ARID1A alterations in two series of patients with UBC. In the first tumor series, we analyze exons 2-20 in 52 primary UBC and find that all mutant tumors belong to the aggressive UBC phenotype (high grade non-muscle invasive and muscle invasive tumors) (P = 0.05). In a second series (n = 84), we assess ARID1A expression using immunohistochemistry, a surrogate for mutation analysis, and find that loss of expression increases with higher stage/grade, it is inversely associated with FGFR3 overexpression (P = 0.03) but it is not correlated with p53 overexpression (P = 0.30). We also analyzed the expression of cytokeratins in the same set of tumor and find, using unsupervised clustering, that tumors with ARID1A loss of expression are generally KRT5/6-low. In this patient series, loss of ARID1A expression is also associated with worse prognosis, likely reflecting the higher prevalence of losses found in tumors of higher stage and grade. The independent findings in these two sets of patients strongly support the notion that ARID1A inactivation is a key player in bladder carcinogenesis occurring predominantly in FGFR3 wild type tumors.

The genes encoding tyrosine kinase receptors EphB2 and EphB3 are β-catenin and Tcf4 target genes in colorectal cancer (CRC) and in normal intestinal cells 1 , 2 . In the intestinal epithelium, EphB signaling controls the positioning of cell types along the crypt-villus axis 1 . In CRC, EphB activity suppresses tumor progression beyond the earliest stages 3 , 4 . Here we show that EphB receptors compartmentalize the expansion of CRC cells through a mechanism dependent on E-cadherin–mediated adhesion. We demonstrate that EphB-mediated compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrin-B1–positive territories in vitro and in vivo . Our results indicate that CRC cells must silence EphB expression to avoid repulsive interactions imposed by normal ephrin-B1–expressing intestinal cells at the onset of tumorigenesis.

Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen (PSCA) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 (r2 = 0.02, D' = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confidence interval (CI) = 1.06–1.17, P = 5.8 x 10–5] for rs2294008 and OR = 1.07 (95% CI = 1.02–1.13, P = 9.7 x 10–3) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08–1.41, P = 1.8 x 10–3) and there was a significant multiplicative interaction (P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples (n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples (n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA. The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through different mechanisms that influence the control of mRNA expression and interaction with regulatory factors.

Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23–374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent. We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports. In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1·2 (95% CI 0·8–1·7) and 1·9 (1·4–2·7) respectively (p for trend <0·0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1·4 [1·2–1·7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0·008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0·0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0·009). The overall association for GSTM1 was also robust (p<0·0001) and was not modified by smoking status (p=0·86). The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer. Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.

Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I(2) statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [P(GSEA) = 0.0100, P(ARTP) = 0.0020], 'NAD biosynthesis' [P(GSEA) = 0.0018, P(ARTP) = 0.0086], 'NAD salvage' [P(ARTP) = 0.0068], 'Clathrin derived vesicle budding' [P(ARTP) = 0.0018], 'Lysosome vesicle biogenesis' [P(GSEA) = 0.0023, P(ARTP)<0.00012], 'Retrograde neurotrophin signaling' [P(GSEA) = 0.00840], and 'Mitotic metaphase/anaphase transition' [P(GSEA) = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis.