文章：

肿瘤抑制免疫基因治疗逆转免疫治疗耐药性

Tumor suppressor immune gene therapy to reverse immunotherapy resistance 

原文发布日期：2021-08-05 

英文摘要：

While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies. We investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays. The substantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with the complete tumor remissions of both the primary and contralateral tumors. Interestingly, contralateral tumors, which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p < 0.001). None of the monotherapies or doublet treatments induced the complete tumor regressions. Ad-p53 treatment increased interferon, CD8+ T cell, immuno-proteosome antigen presentation, and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune-suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 downregulated genes associated with stromal pathways and IL10 expression identified novel anticancer therapeutic applications. These results imply the ability of Ad-p53 to induce efficacious local and systemic antitumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complementary immune mechanisms of action, which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist, and immune checkpoint inhibitor combination treatment. 

摘要翻译： 

尽管免疫检查点抑制剂正成为多种癌症的标准治疗方案，但大多数患者对这种免疫疗法并无反应。我们需要新方法来克服免疫疗法耐药性。我们在对免疫疗法具有抵抗性的侵袭性B16F10肿瘤模型中，研究了腺病毒p53（Ad-p53）基因疗法联合免疫检查点抑制剂及选择性IL2或IL15 CD122/132激动剂的疗效。为评估潜在作用机制，我们通过Nanostring IO 360检测分析了Ad-p53治疗前后活检组织的基因表达谱变化。"三联"疗法（Ad-p53+CD122/132+抗PD-1）展现出显著协同效应，可诱导原发灶和对侧肿瘤完全消退的潜在治愈效果。值得注意的是，未注射Ad-p53的对侧肿瘤出现显著远端效应，肿瘤体积统计学显著缩小（p<0.001）且生存期延长。所有单药或双药疗法均未能实现肿瘤完全消退。Ad-p53治疗增强了干扰素信号、CD8+ T细胞活性、免疫蛋白酶体抗原呈递和肿瘤炎症基因特征，同时抑制了免疫抑制性TGF-β、β-连环蛋白、巨噬细胞和内皮细胞基因特征，这些变化可能有助于提升免疫检查点抑制剂（CPI）疗效。意外的是，研究发现多个先前未知的、被p53强烈下调的基质通路相关基因和IL10表达基因，为抗癌治疗提供了新靶点。这些结果表明Ad-p53能诱导有效的局部和全身抗肿瘤免疫应答，当与CD122/132激动剂及免疫检查点阻断联用时，可能逆转免疫检查点抑制剂耐药性。我们的发现进一步揭示Ad-p53具有多重互补免疫机制，支持未来开展Ad-p53、CD122/132激动剂与免疫检查点抑制剂三联疗法的临床评估。

原文链接：

Tumor suppressor immune gene therapy to reverse immunotherapy resistance