# Immunogenic Tumor Cell Death Induced by Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer: An Immunohistochemical Analysis

## TL;DR

This study shows that platinum-based chemotherapy can trigger immune responses in bladder cancer patients, potentially improving survival and response to immunotherapy.

## Contribution

The study identifies HMGB1 upregulation as a potential biomarker for chemotherapy-induced immunogenic cell death and improved prognosis in bladder cancer.

## Key findings

- HMGB1 and calreticulin upregulation was significantly higher in NAC-treated patients compared to those without NAC.
- HMGB1 upregulation was associated with longer cancer-specific and overall survival.
- HMGB1 upregulation correlated with better response to immune checkpoint inhibitors in patients with recurrent disease.

## Abstract

Aim: To investigate immunogenic cell death (ICD) induced by platinum-based neoadjuvant chemotherapy (NAC) and its impact on survival outcomes in patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy (RC).

Methods: This study included 45 patients with MIBC who underwent RC with (n = 25) or without NAC (n = 20). Induction of ICD in MIBC was assessed by comparing immunohistochemical analyses of two ICD-related proteins, high-mobility group box 1 (HMGB1) and calreticulin, between transurethral resection (TUR) and matched RC specimens. Clinicopathologic data, including the upregulation of ICD-related proteins, were correlated with survival outcomes after RC.

Results: Upregulation of HMGB1 and calreticulin from TUR to matched RC specimens was observed in 11 (44%) and 12 (48%) of 25 NAC-treated patients, respectively, whereas it was detected in only two (8%) and one (4%) patients without NAC (P = 0.03 and P = 0.01, respectively). Upregulation of HMGB1 was significantly associated with longer cancer-specific survival (CSS) and overall survival (P < 0.01 and P = 0.02, respectively). Upregulation of HMGB1 and histological subtype (P = 0.03 and P = 0.05, respectively) were independent prognostic factors for CSS. Furthermore, among NAC-treated patients with recurrent disease, upregulation of HMGB1 tended to correlate with a better response to subsequent immune checkpoint inhibitor therapy and longer survival (P = 0.07).

Conclusions: Our findings suggest that platinum-based NAC induces ICD in MIBC. Upregulation of HMGB1 may serve as a marker of chemotherapy-induced ICD and as a potential prognostic biomarker after RC.