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    • NPRL2 Gene Therapy Induces Effective Antitumor Immunity in KRAS/STK11 Mutant Anti-Pd1 Resistant Metastatic Non-Small Cell Lung Cancer (NSCLC) in a Humanized Mouse Model

    Ismail M Meraz,Mourad Majidi, Renduo Song,Feng Meng, Lihui Gao,Qi Wang,Jing Wang, Elizabeth J Shpall,Jack A Roth

    eLife（2025）

    Cited 0|Views3
    Abstract
    Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11mt/aPD1R tumors but was synergistic in KRASwt/aPD1S H1299. NPRL2 also showed a significant antitumor effect on KRASmt/aPD1R LLC2 syngeneic-tumors. The antitumor effect was correlated with increased infiltration of human cytotoxic-T, HLA-DR+DC, CD11c+DC, and downregulation of myeloid and regulatory-T cells in TME. Antitumor effect was abolished upon in-vivo depletion of CD8-T, macrophages, and CD4-T cells whereas remained unaffected upon NK-cell depletion. A distinctive protein-expression profile was found after NPRL2 treatment. IFNγ, CD8b, and TBX21 associated with T-cell functions were significantly increased, whereas FOXP3, TGFB1/B2, and IL-10RA were strongly inhibited by NPRL2. A list of T-cell co-inhibitory molecules was also downregulated. Restoration of NPRL2 exhibited significantly slower tumor growth in humanized-mice, which was associated with increased presence of human cytotoxic-T, and DC and decreased percentage of Treg, MDSC, and TAM in TME. NPRL2-stable cells showed a substantial increase in colony-formation inhibition and heightened sensitivity to carboplatin. Stable-expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR signaling. Taken-together, NPRL2 gene-therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen-presentation and cytotoxic immune-cell activation.
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    nprl2 gene therapy,NSCLC,anti-PD1 resistance,KRAS/STK11 mutation,humanized mouse model
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    【要点】：研究显示，NPRL2基因疗法通过增强抗原呈递和激活细胞毒性免疫细胞，在人类化小鼠模型中有效诱导KRAS/STK11突变型抗PD-1耐药转移性非小细胞肺癌（NSCLC）的抗肿瘤免疫反应。
    

    【方法】：研究者通过将新鲜人脐血来源的CD34干细胞移植到亚致死照射的NSG小鼠中，建立了人类化小鼠模型，并在这些模型中研究了NPRL2基因疗法对KRAS/STK11mt/aPD1R A549细胞诱导的肺转移的治疗效果。
    

    【实验】：实验使用人类化小鼠和非人类化小鼠，将KRAS/STK11mt/aPD1R A549细胞移植到小鼠中，随后用NPRL2治疗，并与或不与pembrolizumab联合使用。结果显示，NPRL2治疗显著减少了肺转移，而pembrolizumab单独使用无效。NPRL2治疗的效果在人类化小鼠中更为显著。此外，NPRL2对KRASmt/aPD1R LLC2同系肿瘤也显示出显著的抗肿瘤效果。实验结果与TME中人类细胞毒性T细胞、HLA-DR+DC、CD11c+DC的浸润增加以及髓样和调节T细胞的下调相关。在CD8-T细胞、巨噬细胞和CD4-T细胞耗尽后，抗肿瘤效果消失，而NK细胞耗尽不影响效果。NPRL2治疗后，发现独特的蛋白质表达谱变化，与T细胞功能相关的IFNγ、CD8b、TBX21显著增加，而FOXP3、TGFB1/B2、IL-10RA被强烈抑制。NPRL2稳定的细胞对卡铂的敏感性增强，并抑制了MAPK和AKT-mTOR信号通路。