Granzyme B PET imaging of immune-mediated tumor killing as a tool for understanding immunotherapy response
Granzyme B PET imaging of immune-mediated tumor killing as a tool for understanding immunotherapy response
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DOI：
10.1136/jitc-2019-000291
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Mahmood, Umar
中科院分区：
文献类型：
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作者：
LaSalle, Thomas;Austin, Emily E.;Mahmood, Umar
背景癌症免疫治疗研究正在扩大，包括对治疗反应和耐药性机制的更深入了解。治疗期间识别促肿瘤和抗肿瘤免疫的驱动因素为有效的替代或联合免疫疗法提供了新策略。目前，组织或血液样本被收集和分析，然后基于可能在组织收集后数月或数年发生的临床终点进行二分。虽然总生存期最终是期望的临床结果，但这种二分法未能纳入抗肿瘤反应期间可能发生的细微差别。由于未能在采样时直接测量免疫激活，肿瘤可能被错误分类，并可能掩盖重要的生物信息。非侵入性技术，如正电子发射断层扫描（PET），允许全球和定量测量癌症的特定过程，并广泛用于临床，以帮助管理diseases.Methods我们以前已经开发出一种新的PET剂，可以非侵入性定量颗粒酶B释放在肿瘤中，并已证明其能够预测响应检查点抑制剂治疗在多个小鼠癌症模型。在这里，我们使用颗粒酶B释放的定量测量作为免疫细胞活化的直接和时间匹配的标志物，以确定与肿瘤和肿瘤引流淋巴结中有效的检查点抑制剂治疗相关的免疫细胞类型和细胞因子。其影响免疫细胞亚群和细胞因子释放。虽然每个肿瘤的免疫细胞活化和炎症的功能不同的途径，他们也有共同点，最终导致颗粒酶B释放和肿瘤killing.Conclusions这些结果表明，离散的肿瘤免疫微环境可以确定在响应和非响应肿瘤，并提供了战略目标的干预，以克服检查点抑制剂的耐药性。
Background Cancer immunotherapy research is expanding to include a more robust understanding of the mechanisms of treatment response and resistance. Identification of drivers of pro-tumor and anti-tumor immunity during treatment offers new strategies for effective alternative or combination immunotherapies. Currently, tissue or blood samples are collected and analyzed, then dichotomized based on clinical end points that may occur months or years after tissue is collected. While overall survival is ultimately the desired clinical outcome, this dichotomization fails to incorporate the nuances that may occur during an anti-tumor response. By failing to directly measure immune activation at the time of sampling, tumors may be misclassified and potentially obscure important biological information. Non-invasive techniques, such as positron emission tomography (PET), allow for global and quantitative measurements of cancer specific processes and are widely used clinically to help manage disease.Methods We have previously developed a novel PET agent that can non-invasively quantify granzyme B release in tumors and have demonstrated its ability to predict response to checkpoint inhibitor therapy in multiple murine models of cancer. Here, we used the quantitative measurement of granzyme B release as a direct and time-matched marker of immune cell activation in order to determine immune cell types and cytokines that correlate with effective checkpoint inhibitor therapy in both tumors and tumor-draining lymph nodes.Results Through PET imaging, we were able to successfully distinguish distinct microenvironments, based on tumor type, which influenced immune cell subpopulations and cytokine release. Although each tumor was marked by functionally distinct pathways of immune cell activation and inflammation, they also shared commonalities that ultimately resulted in granzyme B release and tumor killing.Conclusions These results suggest that discrete tumor immune microenvironments can be identified in both responsive and non-responsive tumors and offers strategic targets for intervention to overcome checkpoint inhibitor resistance.