Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

To assess the prognostic value of the extent of positive surgical margins (PSM) following radical prostatectomy (RP) on biochemical recurrence (BR) with long-term follow-up. This retrospective study analyzed 1275 RPs performed between January 1992 and December 2013 in two university centers in Marseille (France). The inclusion criteria were: follow-up > 24 months, undetectable postoperative prostate-specific antigen (PSA), no seminal vesicle (SV) invasion, no lymph node invasion confirmed by surgery (pN0) or imaging (pNx), and no neoadjuvant or adjuvant treatment. BR was defined by PSA level ≥ 0.2 ng/mL on two successive samples. We included 189 patients, divided into two groups: - Focal PSM (fPSM): single PSM (sPSM) ≤3 mm; - Extensive PSM (ePSM): sPSM with linear length > 3 mm or several margins regardless of the length. The median follow-up was 101 months (18–283) and the median age was 63 years (46–76). BR occurred in only 12.1% (14/115) of cases involving fPSM and in 54.1% (40/74) of cases involving ePSM. In the multivariate model, ePSM patients were significantly associated with increased BR compared to fPSM (hazard ratio [HR] = 6.11; 95% confidence interval [CI] = 3.25–11.49). The ePSM significantly decreased BR-free survival (p < 0.001) for every patient and every subgroup (pT2, pT3a, pG ≤6, and pG ≥7). The median BR time following RP was significantly shorter for ePSM patients than fPSM (57.2 vs. 89.2 months p < 0.001). With a median 8-year follow-up, ePSM was strongly associated with BR compared to fPSM. Therefore, it seems legitimate to monitor patients with fPSM. In cases of ePSM, adjuvant treatment appears effective.