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Abstract：
OBJECTIVE: Immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) has become first-line therapy for metastatic renal cell carcinoma patients. This study aims to investigate the effect of tumor infiltrating B lymphocytes (TIBs) on the combination therapy.
METHODS: The retrospective analysis was conducted on the clinical records of 115 metastatic clear cell renal cell carcinoma (mccRCC) patients treated with anti-PD-1 antibody plus Axitinib between March 2020 and June 2023. Observation target: objective response rate (ORR), and overall survival (OS), progression-free survival (PFS) and immune profile.
RESULTS: Patients with high TIBs portended lower ORR of the combination therapy (p = 0.033). TIBs was an independent predictor for poorer OS (p = 0.013) and PFS (p = 0.021) in mccRCC patients with combination treatment. TIBs infiltration was associated with more CD4+T (p < 0.001), CD8+T (p < 0.001), M2 macrophages (p = 0.020) and regulatory T cells (Tregs) (p = 0.004). In TIBs high patients, the percentages of PD-1, CTLA-4 and TIM-3 positive rate were significantly increased in CD4+T (p = 0.038, 0.029 and 0.002 respectively) and CD8+T cells (p = 0.006, 0.026 and < 0.001 respectively).
CONCLUSIONS: Our study revealed TIBs infiltration predicted adverse outcomes in mccRCC patients treated with anti-PD-1 antibody plus Axitinib. As a corollary, TIBs positively associated with M2 macrophages and Tregs, leading to subsequent multiple immune checkpoints related exhaustion of T cells. Thus, only PD-1 blockade are inadequate to reverse T cells exhaustion effectively in high TIBs mccRCC patients.
METHODS: The retrospective analysis was conducted on the clinical records of 115 metastatic clear cell renal cell carcinoma (mccRCC) patients treated with anti-PD-1 antibody plus Axitinib between March 2020 and June 2023. Observation target: objective response rate (ORR), and overall survival (OS), progression-free survival (PFS) and immune profile.
RESULTS: Patients with high TIBs portended lower ORR of the combination therapy (p = 0.033). TIBs was an independent predictor for poorer OS (p = 0.013) and PFS (p = 0.021) in mccRCC patients with combination treatment. TIBs infiltration was associated with more CD4+T (p < 0.001), CD8+T (p < 0.001), M2 macrophages (p = 0.020) and regulatory T cells (Tregs) (p = 0.004). In TIBs high patients, the percentages of PD-1, CTLA-4 and TIM-3 positive rate were significantly increased in CD4+T (p = 0.038, 0.029 and 0.002 respectively) and CD8+T cells (p = 0.006, 0.026 and < 0.001 respectively).
CONCLUSIONS: Our study revealed TIBs infiltration predicted adverse outcomes in mccRCC patients treated with anti-PD-1 antibody plus Axitinib. As a corollary, TIBs positively associated with M2 macrophages and Tregs, leading to subsequent multiple immune checkpoints related exhaustion of T cells. Thus, only PD-1 blockade are inadequate to reverse T cells exhaustion effectively in high TIBs mccRCC patients.
摘要：
目的：免疫检查点抑制剂（ICIs）加酪氨酸激酶抑制剂（TKIs）已成为转移性肾细胞癌患者的一线治疗方法。本研究旨在探讨肿瘤浸润B淋巴细胞（TIBs）对联合治疗的影响。
方法：对2020年3月至2023年6月期间接受抗PD-1抗体联合阿西替尼治疗的115例转移性透明细胞肾细胞癌（mccRCC）患者的临床记录进行回顾性分析。观察目标：客观反应率（ORR），和总生存率（OS），无进展生存期（PFS）和免疫谱。
结果：高TIB患者预示联合治疗的ORR较低（p=0.033）。TIB是联合治疗mccRCC患者OS（p=0.013）和PFS（p=0.021）较差的独立预测因子。TIBs浸润与更多的CD4+T相关(p<0.001)，CD8+T（p<0.001），M2巨噬细胞(p=0.020)和调节性T细胞(Tregs)(p=0.004)。在TIBs高患者中，CD4+T细胞(p=0.038、0.029和0.002)和CD8+T细胞(p=0.006、0.026和<0.001)中PD-1、CTLA-4和TIM-3阳性率显著升高。
结论：我们的研究显示TIBs浸润预测了抗PD-1抗体联合阿西替尼治疗mccRCC患者的不良结局。作为一个推论,TIB与M2巨噬细胞和Tregs呈正相关，导致随后的多个免疫检查点相关的T细胞耗尽。因此，仅PD-1阻断不足以有效逆转高TIBsmccRCC患者的T细胞耗竭。
方法：对2020年3月至2023年6月期间接受抗PD-1抗体联合阿西替尼治疗的115例转移性透明细胞肾细胞癌（mccRCC）患者的临床记录进行回顾性分析。观察目标：客观反应率（ORR），和总生存率（OS），无进展生存期（PFS）和免疫谱。
结果：高TIB患者预示联合治疗的ORR较低（p=0.033）。TIB是联合治疗mccRCC患者OS（p=0.013）和PFS（p=0.021）较差的独立预测因子。TIBs浸润与更多的CD4+T相关(p<0.001)，CD8+T（p<0.001），M2巨噬细胞(p=0.020)和调节性T细胞(Tregs)(p=0.004)。在TIBs高患者中，CD4+T细胞(p=0.038、0.029和0.002)和CD8+T细胞(p=0.006、0.026和<0.001)中PD-1、CTLA-4和TIM-3阳性率显著升高。
结论：我们的研究显示TIBs浸润预测了抗PD-1抗体联合阿西替尼治疗mccRCC患者的不良结局。作为一个推论,TIB与M2巨噬细胞和Tregs呈正相关，导致随后的多个免疫检查点相关的T细胞耗尽。因此，仅PD-1阻断不足以有效逆转高TIBsmccRCC患者的T细胞耗竭。
