PO.IM01.10 · 免疫学
T细胞急性淋巴细胞白血病（T-ALL）驱动强大的T细胞应答，可通过aCD40和aPD1联合疗法加以利用
T-cell acute lymphoblastic leukemia (T-ALL) drives robust T cell responses that can be harnessed with aCD40 and aPD1 combination therapy
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摘要 Abstract
中文摘要
T细胞急性淋巴细胞白血病（T-ALL）是一种不成熟T细胞的恶性肿瘤，其特征是低突变负荷和有限的新抗原。尽管生存率有所提高，但标准治疗仍未从强化化疗方案发展而来，该方案毒性极高且复发率高。因此，需要更具靶向性的疗法。免疫疗法（如检查点阻断）旨在利用患者已有的抗肿瘤T细胞，是一种可行的替代方案。然而，由于低肿瘤突变负荷，T-ALL是否对这种方法有反应尚不清楚。我们使用将来自自发性白血病小鼠的CD45.2+ T-ALL细胞移植到免疫健全的CD45.1+宿主中的小鼠模型，随时间研究宿主（CD45.1+）T细胞应答。采用NUR77、RAG敲除、OT-I、OT-II小鼠模型和体外模型，我们确认了白血病特异性、TCR驱动的激活，同时单细胞RNA测序鉴定出扩增的抗肿瘤效应亚群。我们发现T-ALL尽管突变负荷低，仍引发白血病特异性T细胞。免疫分析显示表达PD-1、TOX的效应记忆T细胞升高以及FoxP3+ Tregs，与慢性耗竭和持续免疫应答相符。离体细胞因子检测显示IL-2减少但IFN-gamma产生增加，进一步表明部分耗竭。为确认抗原特异性，我们将T-ALL移植到OT-I和OT-II小鼠中，其固定的TCR识别OVA（在我们的白血病模型中不存在）。这些小鼠缺乏PD-1+TOX+ T细胞，证实在野生型小鼠中观察到的耗竭是白血病特异性的。NUR77转基因分析验证了TCR信号驱动了这种激活。髓系细胞表现出PD-L1上调和抑制性亚群的富集，提示抑制性交互作用约束了白血病特异性T细胞。基于此，我们评估了使用alphaCD40激活髓系抗原呈递细胞和alphaPD-1逆转T细胞耗竭的联合免疫疗法。虽然任一单药治疗均适度延长生存期，但双重治疗诱导了强大、持久的应答，约50%的小鼠达到完全缓解。再攻击实验证实了长期免疫记忆。总之，我们的发现表明尽管抗原性低，T-ALL仍能产生可在治疗上加以利用的白血病特异性T细胞应答。共同靶向髓系激活和PD-1抑制代表了T-ALL一条有前景的免疫治疗途径。
查看英文原文 English abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cells characterized by a low mutational burden and limited neoantigens. Despite improved survival rates, the standard of care has not progressed from an intensive chemotherapy regimen, which is highly toxic with a high relapse rate. Therefore, there is a need for more targeted therapies. Immunotherapy, like checkpoint blockade, that aims to harness the patient's pre-existing anti-tumor T cells, is a viable alternative. However, whether or not T-ALL is responsive to this approach is unknown due to low tumor mutational burden. Using murine models transplanted with CD45.2⁺ T-ALL cells from spontaneously leukemic mice into immune-competent CD45.1⁺ hosts, we investigated host (CD45.1⁺) T-cell responses over time. Employing NUR77, RAG knock-out, OT-I, OT-II mouse models and in vitro models, we confirmed leukemia-specific, TCR-driven activation, while single-cell RNA sequencing identified expanded antitumor effector subsets.We found that T-ALL elicits leukemia-specific T cells despite its low mutational burden. Immune profiling revealed elevated effector-memory T cells expressing PD-1, TOX, and FoxP3⁺ Tregs, consistent with chronic exhaustion and an ongoing immune response. Ex vivo cytokine assays demonstrated reduced IL-2 but increased IFN-gamma production, further indicating partial exhaustion. To confirm antigen specificity, we transplanted T-ALL into OT-I and OT-II mice, whose fixed TCRs recognize OVA (absent in our leukemia model). These mice lacked PD-1⁺TOX⁺ T cells, confirming that exhaustion observed in wild-type mice was leukemia-specific. NUR77 transgenic analyses verified that TCR signaling drove this activation. Myeloid cells exhibited upregulated PD-L1 and enrichment of suppressive subsets, suggesting inhibitory crosstalk restraining leukemia-specific T cells. Based on this, we evaluated combined immunotherapy using alphaCD40 to activate myeloid antigen-presenting cells and alphaPD-1 to reverse T-cell exhaustion. While either monotherapy modestly prolonged survival, dual treatment induced robust, durable responses with ~50% of mice achieving complete remission. Re-challenge experiments confirmed long-term immune memory. Collectively, our findings demonstrate that despite low antigenicity, T-ALL can generate leukemia-specific T-cell responses that can be therapeutically harnessed. Co-targeting myeloid activation and PD-1 inhibition represents a promising immunotherapeutic avenue for T-ALL.
利益披露 Disclosure
F. Alabi, None..
A. Somma, None..
T. Triplett, None.