Multiomic analysis for optimization of combined focal and immunotherapy protocols in murine pancreatic cancer.
Multiomic analysis for optimization of combined focal and immunotherapy protocols in murine pancreatic cancer.
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DOI：
10.7150/thno.73218
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Ferrara KW
中科院分区：
文献类型：
--
作者：
Wang J;Fite BZ;Kare AJ;Wu B;Raie M;Tumbale SK;Zhang N;Davis RR;Tepper CG;Aviran S;Newman AM;King DA;Ferrara KW
背景资料：尽管结合局部和全身组分的组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）可能影响免疫功效。方法：我们设计并评价了结合磁共振引导聚焦超声（MRgFUS）消融和抗体治疗乳腺癌和胰腺癌的治疗策略。通过单细胞测序、光谱流式细胞术和组织学分析的组合，我们分析了免疫抑制的KPC（Kras+/LSL-G12 D; Trp 53 +/LSL-R172 H; Pdx 1-Cre）胰腺癌（MT4）模型和具有更大比例的淋巴细胞、自然杀伤细胞和活化树突状细胞的致密上皮neu缺失（NDL）HER 2+乳腺癌模型。然后，我们进行了基因本体分析，光谱和数字细胞术，以评估对联合免疫疗法的免疫应答以及与生存研究的相关性。测试结果：基于基因本体分析，将消融添加到免疫疗法中丰富了胰腺癌模型中的免疫细胞迁移途径，并广泛丰富了乳腺癌模型中的伤口愈合途径。使用CIBERSORTx数字细胞术，aCD 40 + aPD-1免疫疗法组合增强了两种模型中的树突状细胞活化。在MT4 TME中，添加aCD 40抗体和检查点抑制剂（aPD-1和aCTLA-4）的组合与消融是协同的，增加了远端肿瘤中活化的自然杀伤细胞和T细胞。此外，免疫治疗的消融上调了关键的Ly 6c骨髓重塑表型，增强了T细胞效应子功能，并增加了多达100倍的颗粒酶和蛋白酶编码基因。消融结合免疫疗法然后在MT4模型中比单独免疫疗法更大程度地延长存活。结论：总之，TME分析为成功的多组分治疗方案提供了信息，该方案包括消融和促进TME的分化，其中消融是最有效的。
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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影响因子：
4.6
作者：
Fite BZ;Wang J;Kare AJ;Ilovitsh A;Chavez M;Ilovitsh T;Zhang N;Chen W;Robinson E;Zhang H;Kheirolomoom A;Silvestrini MT;Ingham ES;Mahakian LM;Tam SM;Davis RR;Tepper CG;Borowsky AD;Ferrara KW
通讯作者：
Ferrara KW
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
6.7
作者：
Anzidei, Michele;Marincola, Beatrice Cavallo;Napoli, Alessandro
通讯作者：
Napoli, Alessandro
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF