Predictive value of toll-like receptors, myeloid differentiation factor 88, and nuclear factor kappa-B regarding the response to Bacillus Calmette-Guérin intravesical therapy in patients with high-risk non-muscle-invasive bladder cancer: A controlled cohort clinical study.

BACKGROUND

Intravesical Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy for high-risk non-muscle-invasive bladder cancer (HR-NMIBC). Toll-like receptors (TLRs) modulate the BCG immune response. Myeloid differentiation factor 88 (MyD88) is a canonical adapter for TLR signaling pathways, which ultimately activates the nuclear factor kappa-B (NF-κB) transcription factor, triggering cytokine expression and immune activation. Validated biomarkers to detect recurrences or progression of T1G3 bladder cancer (BC) are lacking.

PURPOSE: Our study aimed to analyze the role of TLRs, MyD88, and NF-κB in predicting the response to BCG immunotherapy in HR-NMIBC.

METHODS

The study enrolled 100 T1G3 NMIBC patients and 50 controls. TLR2, TLR4, MyD88, and NF-κB gene expression were evaluated, along with TLR4 and MyD88 immunohistochemical (IHC) assays. Gene expression levels were compared between BCG responders and BCG non-responders. Univariate and multivariate logistic regression analyses identified both dependent and independent predictors of BCG non-response. Cox proportional-hazard regression was used for analyses of recurrence and progression-free survival.

RESULTS

In our cohort, 42 patients developed recurrence only, 16 experienced progression only, and 4 progressed after an initial recurrence; they were considered BCG non-responders. BCG responders exhibited significantly elevated TLR2, TLR4, MyD88, and NF-κB gene expression, alongside significantly higher TLR4 and MyD88 protein expression. Low NF-κB gene expression as well as diminished expression of the TLR4 gene and protein were significant independent predictors of high recurrence and progression.

CONCLUSION

TLR2, TLR4, MyD88, and NF-κB expressions can be considered beneficial markers for predicting BCG response in HR-NMIBC.