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Abstract：
BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Pathologic complete response (pCR) is associated with favorable outcomes, but only 30%-40% of patients achieve that response. The aim of this study is to investigate the role played by the Tumor and Immune Microenvironment (TIME) in association with the clinical outcome of patients with MIBC undergoing NAC.
METHODS: Nineteen patients received NAC and were classified as pCR (n = 10) or non-pCR (n = 9). Bulk RNA-seq and immune protein evaluations using Digital Spatial Profiling (DSP) were performed on formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before NAC (baseline). Immunohistochemistry (IHC) evaluation focused on CD3 and CD20 expression was performed on baseline and end-of-treatment (EOT) FFPEs. Baseline peripheral blood was assessed for lymphocyte and neutrophil counts. Kaplan-Meier analyses and Cox PH regression models were used for survival analyses (OS).
RESULTS: In the periphery, pCR patients showed lower neutrophil counts, and neutrophil/ lymphocyte ratio (NLR) when compared to non-pCR patients. In the tumor microenvironment (TME), gene expression analysis and protein evaluations highlighted an abundance of B cells and CD3+ T cells in pCR versus non-pCR patients. On the contrary, increased protein expression of ARG1+ cells, and cells expressing immune checkpoints such as LAG3, ICOS, and STING were observed in the TME of patients with non-pCR.
CONCLUSIONS: In the current study, we demonstrated that lower NLR levels and increased CD3+ T cells and B cell infiltration are associated with improved response and long-term outcomes in patients with MIBC receiving NAC. These findings suggest that the impact of immune environment should be considered in determining the clinical outcome of MIBC patients treated with NAC.
METHODS: Nineteen patients received NAC and were classified as pCR (n = 10) or non-pCR (n = 9). Bulk RNA-seq and immune protein evaluations using Digital Spatial Profiling (DSP) were performed on formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before NAC (baseline). Immunohistochemistry (IHC) evaluation focused on CD3 and CD20 expression was performed on baseline and end-of-treatment (EOT) FFPEs. Baseline peripheral blood was assessed for lymphocyte and neutrophil counts. Kaplan-Meier analyses and Cox PH regression models were used for survival analyses (OS).
RESULTS: In the periphery, pCR patients showed lower neutrophil counts, and neutrophil/ lymphocyte ratio (NLR) when compared to non-pCR patients. In the tumor microenvironment (TME), gene expression analysis and protein evaluations highlighted an abundance of B cells and CD3+ T cells in pCR versus non-pCR patients. On the contrary, increased protein expression of ARG1+ cells, and cells expressing immune checkpoints such as LAG3, ICOS, and STING were observed in the TME of patients with non-pCR.
CONCLUSIONS: In the current study, we demonstrated that lower NLR levels and increased CD3+ T cells and B cell infiltration are associated with improved response and long-term outcomes in patients with MIBC receiving NAC. These findings suggest that the impact of immune environment should be considered in determining the clinical outcome of MIBC patients treated with NAC.
摘要：
背景：以顺铂为基础的新辅助化疗（NAC）和膀胱切除术是肌层浸润性膀胱癌（MIBC）患者的标准治疗方法。病理完全缓解（pCR）与有利的结果相关，但只有30％-40％的患者达到这种反应。这项研究的目的是研究肿瘤和免疫微环境（TIME）与接受NAC的MIBC患者的临床结果相关的作用。
方法：19例患者接受NAC治疗，分为pCR（n=10）或非pCR（n=9）。使用数字空间分析(DSP)对在NAC(基线)之前收集的福尔马林固定的石蜡包埋的(FFPE)肿瘤活检进行大量RNA-seq和免疫蛋白评估。在基线和治疗结束(EOT)FFPE上进行聚焦于CD3和CD20表达的免疫组织化学(IHC)评估。评估基线外周血的淋巴细胞和中性粒细胞计数。Kaplan-Meier分析和CoxPH回归模型用于生存分析(OS)。
结果：在外围，pCR患者显示中性粒细胞计数较低，与非pCR患者相比，中性粒细胞/淋巴细胞比率（NLR）。在肿瘤微环境（TME）中，基因表达分析和蛋白质评估强调了pCR与非pCR患者中B细胞和CD3+T细胞的丰度。相反,ARG1+细胞的蛋白质表达增加，和表达免疫检查点的细胞，如LAG3，ICOS，在非pCR患者的TME中观察到STING。
结论：在当前的研究中，我们证明,在接受NAC的MIBC患者中,较低的NLR水平和增加的CD3+T细胞和B细胞浸润与改善的应答和长期结局相关.这些发现表明，在确定接受NAC治疗的MIBC患者的临床结局时，应考虑免疫环境的影响。
方法：19例患者接受NAC治疗，分为pCR（n=10）或非pCR（n=9）。使用数字空间分析(DSP)对在NAC(基线)之前收集的福尔马林固定的石蜡包埋的(FFPE)肿瘤活检进行大量RNA-seq和免疫蛋白评估。在基线和治疗结束(EOT)FFPE上进行聚焦于CD3和CD20表达的免疫组织化学(IHC)评估。评估基线外周血的淋巴细胞和中性粒细胞计数。Kaplan-Meier分析和CoxPH回归模型用于生存分析(OS)。
结果：在外围，pCR患者显示中性粒细胞计数较低，与非pCR患者相比，中性粒细胞/淋巴细胞比率（NLR）。在肿瘤微环境（TME）中，基因表达分析和蛋白质评估强调了pCR与非pCR患者中B细胞和CD3+T细胞的丰度。相反,ARG1+细胞的蛋白质表达增加，和表达免疫检查点的细胞，如LAG3，ICOS，在非pCR患者的TME中观察到STING。
结论：在当前的研究中，我们证明,在接受NAC的MIBC患者中,较低的NLR水平和增加的CD3+T细胞和B细胞浸润与改善的应答和长期结局相关.这些发现表明，在确定接受NAC治疗的MIBC患者的临床结局时，应考虑免疫环境的影响。
