CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Effect of Annexin A2 on prognosis and sensitivity to immune checkpoint plus tyrosine kinase inhibition in metastatic renal cell carcinoma.
Effect of Annexin A2 on prognosis and sensitivity to immune checkpoint plus tyrosine kinase inhibition in metastatic renal cell carcinoma.
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ANXA2 上调与接受 IO + TKI 治疗的 RCC 患者较差的 PFS 和治疗耐药相关，并与 T 细胞耗竭有关。整合的 RF 评分可对从 IO + TKI 治疗中获益的患者进行分层。
免疫治疗（IO）联合酪氨酸激酶抑制剂（TKI）是晚期肾细胞癌（RCC）的一线推荐方案，但尚无获批的生物标志物。膜联蛋白A2（ANXA2）可诱导肿瘤免疫逃逸。
两个独立的接受IO + TKI治疗的晚期RCC队列被用于生存分析（ZS-MRCC，n = 45；Javelin-101，n = 726）。ANXA2表达通过RNA测序确定。ANXA2对肿瘤微环境的影响通过RNA测序、流式细胞术和免疫组织化学在两个局限性RCC数据集中评估（ZS-HRRCC，n = 40；TCGA-KIRC，n = 530）。
ANXA2在IO + TKI治疗无应答者中表达上调（p = 0.027）。高ANXA2组在ZS-MRCC队列（HR，2.348；95% CI 1.084-5.085；P = 0.025）和Javelin-101队列（HR，1.472；95% CI 1.043-2.077；P = 0.027）中均显示较差的无进展生存期（PFS）。多因素Cox回归确定ANXA2为独立预后因素（HR，2.619；95% CI 1.194-5.746；P = 0.016）。高ANXA2与granzyme B + CD8 + T细胞比例降低相关（Spearman's ρ = - 0.40，P = 0.01），并与TIM-3 +（Spearman's ρ = 0.43，P < 0.001）和CTLA4 +（Spearman's ρ = 0.49，P < 0.001）TIL（肿瘤浸润淋巴细胞）增加相关。进一步通过整合ANXA2和免疫基因构建了随机森林（RF）评分，该评分可对将从IO + TKI治疗中获益的患者进行分层（低RF评分，IO + TKI vs TKI，HR = 0.453，95% CI 0.328-0.626；高RF评分，IO + TKI vs TKI，HR = 0.877，95% CI 0.661-1.165；交互作用P = 0.003）。
Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) therapy is the first-line recommendation for advanced renal cell carcinoma (RCC), but no biomarker has been approved for it. Annexin A2 (ANXA2) can induce immune escape in tumors.
Two independent cohorts of advanced RCC treated by IO + TKI were utilized for survival analysis (ZS-MRCC, n = 45; Javelin-101, n = 726). ANXA2 expression was determined by RNA-sequencing. The impact of ANXA2 on the tumor microenvironment was assessed by RNA-sequencing, flow cytometry and immunohistochemistry in two localized RCC datasets (ZS-HRRCC, n = 40; TCGA-KIRC, n = 530).
ANXA2 was upregulated in non-responders of IO + TKI therapy (p = 0.027). High-ANXA2 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (HR, 2.348; 95% CI 1.084-5.085; P = 0.025) and the Javelin-101 cohort (HR, 1.472; 95% CI 1.043-2.077; P = 0.027). Multivariate Cox regression determined ANXA2 as an independent prognostic factor (HR, 2.619; 95% CI 1.194-5.746; P = 0.016). High-ANXA2 was correlated with decreased proportion of granzyme B + CD8 + T cells (Spearman's ρ = - 0.40, P = 0.01), and increased TIM-3 + (Spearman's ρ = 0.43, P < 0.001) and CTLA4 + (Spearman's ρ = 0.49, P < 0.001) tumor-infiltrating lymphocytes. A random forest (RF) score was further build by integrating ANXA2 and immune genes, which stratified patients who would benefit from IO + TKI therapy (low-RF score, IO + TKI vs TKI, HR = 0.453, 95% CI 0.328-0.626; high-RF score, IO + TKI vs TKI, HR = 0.877, 95% CI 0.661-1.165; interaction P = 0.003).
Upregulated ANXA2 was associated with poor PFS and therapeutic resistance in RCC treated by IO + TKI therapy, and related with T cell exhaustion. The integrated RF score could stratify patients who would benefit from IO + TKI therapy.
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