Baseline FFPE tumor tissue was analyzed using PD-L1 immunohistochemistry (n=51), whole-exome and transcriptome sequencing (both n=53) and correlated with response. Baseline infiltration of CD8+ T-cells (n=51) and at cystectomy (n=42) was examined. ScRNAseq of CD3+ T-cells was conducted on on-treatment resection tissue of two responders to ipilimumab-high to explore characteristics of CD8+ T-cells within the TME.
Our data indicate that TMB, PD-L1 and TGFβ are potential biomarkers for response to ipilimumab plus nivolumab in stage III urothelial cancer. An inflammatory TME might be relevant for responding to ipilimumab-low. We found that in responders to ipilimumab-high, TCF7+CD8+ T-cells accumulated in the TME. ScRNAseq in two responders suggested that TCF7+CD8+ T-cells express genes associated with immunological memory formation and T-cell homing.
High tumor mutational burden (TMB) and PD-L1 positivity were associated with response to ipilimumab plus nivolumab. Non-responding patients exhibited increased expression of a TGFβ signature. We observed increased transcription of the g2m checkpoint and e2f target in responders to ipilimumab-high and enhanced transcription of IFN-α and -γ hallmarks in responders to ipilimumab-low. CD8+TCF7+ T-cells accumulated in the TME of responders to ipilimumab-high. ScRNAseq of CD8+TCF7+ T-cells demonstrated enhanced expression of IL7R, CCR7, GPR15, XCL1, SELL and LEF1.
In NABUCCO, safety and efficacy of preoperative ipilimumab plus nivolumab were assessed in stage III urothelial cancer. Encouraging responses were achieved and ipilimumab 3 mg/kg (ipilimumab-high) appeared more effective than ipilimumab 1 mg/kg (ipilimumab-low). We explored ipilimumab plus nivolumab response biomarkers and tumor micro environment (TME) treatment dynamics.
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