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-fi ling 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 cor-related with clinical benefi t. 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- specifi c CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefi t. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.

Automated summary

CD4+ T cells and PD-L1 expression are correlated with the efficacy of immunotherapy drugs, which is important for the treatment of bladder cancer patients.