肿瘤细胞治疗研究
英文原题：Multiomic analysis for optimization of combined focal and immunotherapy protocols in murine pancreatic cancer.
TME分析指导了一种成功的多组分治疗方案，该方案结合了消融治疗，并促进了TME的分化，在此过程中消融治疗最为有效。
背景：尽管结合局部和全身成分的联合免疫疗法在治疗实体瘤方面显示出有希望的结果，但不同的肿瘤微环境（TME）可能影响免疫治疗疗效。方法：我们设计并评估了结合磁共振引导聚焦超声（MRgFUS）消融和抗体疗法的乳腺癌和胰腺癌治疗策略。通过结合单细胞测序、光谱流式细胞术和组织学分析，我们分析了一个免疫抑制的KPC（Kras +/LSL-G12D ; Trp53 +/LSL-R172H ; Pdx1-Cre）胰腺腺癌（MT4）模型和一个密集上皮neu缺失（NDL）HER2 + 乳腺腺癌模型，后者具有较高比例的淋巴细胞、NK 细胞和活化树突状细胞。随后我们进行了基因本体分析、光谱和数字流式细胞术，以评估对联合免疫疗法的免疫反应及其与生存研究的相关性。结果：基于基因本体分析，在胰腺癌模型中，将消融加入免疫治疗富集了免疫细胞迁移通路，而在乳腺癌模型中则广泛富集了伤口愈合通路。通过CIBERSORTx数字流式细胞术，aCD40 + aPD-1免疫治疗组合在两种模型中均增强了树突状细胞活化。在MT4 TME中，将aCD40抗体和检查点抑制剂（aPD-1和aCTLA-4）联合消融具有协同作用，增加了远处肿瘤中的活化NK 细胞和T细胞。此外，消融联合免疫治疗上调了增强T细胞效应功能的关键Ly6c髓系重塑表型，并使颗粒酶和蛋白酶编码基因增加了多达100倍。消融联合免疫治疗在MT4模型中比单独免疫治疗更大程度地延长了生存期。结论：总之，TME分析指导了一个成功的包含消融的多组分治疗方案，并促进了对消融最有效的TMEs的区分。
Background: Although combination immunotherapies incorporating local and systemic components have shown promising results in treating solid tumors, varied tumor microenvironments (TMEs) can impact immunotherapeutic efficacy. Method: We designed and evaluated treatment strategies for breast and pancreatic cancer combining magnetic resonance-guided focused ultrasound (MRgFUS) ablation and antibody therapies. With a combination of single-cell sequencing, spectral flow cytometry, and histological analyses, we profiled an immune-suppressed KPC (Kras +/LSL-G12D ; Trp53 +/LSL-R172H ; Pdx1-Cre) pancreatic adenocarcinoma (MT4) model and a dense epithelial neu deletion (NDL) HER2 + mammary adenocarcinoma model with a greater fraction of lymphocytes, natural killer cells and activated dendritic cells. We then performed gene ontology analysis, spectral and digital cytometry to assess the immune response to combination immunotherapies and correlation with survival studies. Result: Based on gene ontology analysis, adding ablation to immunotherapy enriched immune cell migration pathways in the pancreatic cancer model and extensively enriched wound healing pathways in the breast cancer model. With CIBERSORTx digital cytometry, aCD40 + aPD-1 immunotherapy combinations enhanced dendritic cell activation in both models. In the MT4 TME, adding the combination of aCD40 antibody and checkpoint inhibitors (aPD-1 and aCTLA-4) with ablation was synergistic, increasing activated natural killer cells and T cells in distant tumors. Furthermore, ablation with immunotherapy upregulated critical Ly6c myeloid remodeling phenotypes that enhance T-cell effector function and increased granzyme and protease encoding genes by as much as 100-fold. Ablation combined with immunotherapy then extended survival in the MT4 model to a greater extent than immunotherapy alone. Conclusion: In summary, TME profiling informed a successful multicomponent treatment protocol incorporating ablation and facilitated differentiation of TMEs in which ablation is most effective.
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