Escherichia coli–Specific CXCL13-Producing T_FH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle- Invasive Bladder Cancer

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Pro-filing tumor and blood samples, we found that follicular helper CD4⁺T cells (T_FH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. T_FH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory T_FH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4⁺CD38⁺T_FH residing in bladder tissues cor-related with clinical benefit. Finally, T_FH 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 T_FH 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.