Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome

BACKGROUND: Whereas neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy remains the standard treatment for patients with muscle-invasive bladder cancer (MIBC), increasing evidence suggests that checkpoint inhibitors, either alone or in combination with chemotherapy, are effective in the (neo)adjuvant setting. The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in MIBC. METHODS: Tumor tissue of 81 patients was used, including 60 patients treated with NAC and 21 patients undergoing upfront cystectomy. Multiplex immunohistochemistry was performed to assess CD3(+), CD3(+)CD8(+), CD3(+)CD8(−)FoxP3(−), CD3(+)FoxP3(+), and CD20(+) cells. Patients were classified into a favorable or unfavorable outcome group based on the development of a recurrence within a year. RESULTS: The density of intratumoral CD3(+) T cells decreased following NAC in patients with a recurrence at one year, while it remained stable in patients without a recurrence (median fold change 0.6 [95CI 0.3; 1.0] versus 1.0 [95CI 0.6; 2.2]). This decrease was mainly attributable to a decrease in CD3(+)CD8(−)FoxP3(−) and CD3(+)FoxP3(+) T cells and was not observed in patients with an early recurrence after upfront cystectomy. Additionally, in cystectomy tissue of patients treated with NAC, median CD3(+) and CD3(+)CD8(+) T cell densities were significantly lower in patients with versus patients without a recurrence (CD3: 261. cells/mm(2) [95CI 22.4; 467.2]; CD8: 189.6 cells/mm(2) [95CI 2.0;462.0]). CONCLUSION: T cell density decreases following NAC in MIBC patients with poor clinical outcome. Further research is needed to investigate whether this decrease in T cell density affects the efficacy of subsequent checkpoint inhibitors. PRÉCIS: The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in patients with MIBC. We reveal a decline in intratumoral CD3(+) T cell density following NAC in patients with an early recurrence. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-022-03234-0.