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Background <p>The primary challenges in CD19-specific chimeric antigen receptor T-cell (CD19 CAR T) therapy for patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL) are non-response and relapse; it is urgent to reveal these mechanisms. Neutrophils play a critical role in the immunosuppressive tumor microenvironment (TME), which can hinder CAR T efficacy. Our previous research identified a subset of immunosuppressive neutrophils with a special phenotype (CD14<sup>−</sup>CD10<sup>−</sup>CD45<sup>−</sup>HLA-DR<sup>−</sup>SSC<sup>++</sup>, termed CD10<sup>−</sup> neuts), which suppress T cell function. Therefore, we speculate that CD10<sup>−</sup> neuts may also influence CAR T efficacy, and this study aims to clinically validate this hypothesis.</p> Methods <p>We enrolled 44 patients with r/r B-ALL undergoing CD19 CAR T therapy and 47 healthy controls (HCs). Peripheral blood samples were obtained prior to CAR T infusion to detect CD10<sup>−</sup> neuts levels by flow cytometry. Key parameters included the percentage of CD10<sup>−</sup> neuts in neutrophils (CD10<sup>−</sup> neuts/neutrophils), in all nucleated cells (CD10<sup>−</sup> neuts/nucleated cells), and the absolute count of CD10<sup>−</sup> neuts. We analyzed the correlations between these indicators and therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cell persistence time.</p> Results <p>CD10<sup>−</sup> neuts levels were significantly elevated in patients with r/r B-ALL compared to HCs. Additionally, non-responding patients exhibited higher CD10<sup>−</sup> neuts levels than those in remission. Specifically, CD10<sup>−</sup> neuts/neutrophils, CD10<sup>−</sup> neuts/nucleated cells, and absolute CD10<sup>−</sup> neuts count were 64.44% vs. 25.43% (<i>p</i> = 0.004), 28.61% vs. 9.81% (<i>p</i> = 0.018), and 766.1/μL vs. 152.9/μL (<i>p</i> = 0.04), respectively. Among these indices, only CD10<sup>−</sup> neuts/neutrophils emerged as an independent risk factor for CAR T response (OR = 19.8, <i>p</i> = 0.013), relapse (HR = 4.704, <i>p</i> = 0.004), and survival (HR = 6.417, <i>p</i> = 0.001). Patients with CD10<sup>−</sup> neuts/neutrophils ≥ 21.57% demonstrated significantly shorter RFS and OS compared to those with lower levels (<i>p</i> = 0.001; <i>p</i> = 0.0002). Furthermore, CD10<sup>−</sup> neuts/neutrophils were negatively correlated with the persistence time of CAR T cells.</p> Conclusions <p>As one of the key factors in the TME, abnormally elevated CD10<sup>−</sup> neuts correlate with CAR T therapy resistance. Targeting these neutrophils could enhance the effectiveness of CAR T treatment.</p>

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Elevated CD10− neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • Jinli Zhu,
  • Ji Zhou,
  • Xue Liang,
  • Furun An,
  • Yangyang Ding,
  • Xunyi Jiao,
  • Meng Xiao,
  • Fan Wu,
  • Yingwei Li,
  • Hao Xiao,
  • Ying Pan,
  • Huiping Wang,
  • Zhimin Zhai

摘要

Background

The primary challenges in CD19-specific chimeric antigen receptor T-cell (CD19 CAR T) therapy for patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL) are non-response and relapse; it is urgent to reveal these mechanisms. Neutrophils play a critical role in the immunosuppressive tumor microenvironment (TME), which can hinder CAR T efficacy. Our previous research identified a subset of immunosuppressive neutrophils with a special phenotype (CD14−CD10−CD45−HLA-DR−SSC++, termed CD10− neuts), which suppress T cell function. Therefore, we speculate that CD10− neuts may also influence CAR T efficacy, and this study aims to clinically validate this hypothesis.

Methods

We enrolled 44 patients with r/r B-ALL undergoing CD19 CAR T therapy and 47 healthy controls (HCs). Peripheral blood samples were obtained prior to CAR T infusion to detect CD10− neuts levels by flow cytometry. Key parameters included the percentage of CD10− neuts in neutrophils (CD10− neuts/neutrophils), in all nucleated cells (CD10− neuts/nucleated cells), and the absolute count of CD10− neuts. We analyzed the correlations between these indicators and therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cell persistence time.

Results

CD10− neuts levels were significantly elevated in patients with r/r B-ALL compared to HCs. Additionally, non-responding patients exhibited higher CD10− neuts levels than those in remission. Specifically, CD10− neuts/neutrophils, CD10− neuts/nucleated cells, and absolute CD10− neuts count were 64.44% vs. 25.43% (p = 0.004), 28.61% vs. 9.81% (p = 0.018), and 766.1/μL vs. 152.9/μL (p = 0.04), respectively. Among these indices, only CD10− neuts/neutrophils emerged as an independent risk factor for CAR T response (OR = 19.8, p = 0.013), relapse (HR = 4.704, p = 0.004), and survival (HR = 6.417, p = 0.001). Patients with CD10− neuts/neutrophils ≥ 21.57% demonstrated significantly shorter RFS and OS compared to those with lower levels (p = 0.001; p = 0.0002). Furthermore, CD10− neuts/neutrophils were negatively correlated with the persistence time of CAR T cells.

Conclusions

As one of the key factors in the TME, abnormally elevated CD10− neuts correlate with CAR T therapy resistance. Targeting these neutrophils could enhance the effectiveness of CAR T treatment.