Proteomic determinants of response to checkpoint blockade in malignant pleuralmesothelioma

项目摘要/摘要 恶性胸膜间皮瘤(MPM)是一种致命的肺部衬里癌症，已超过标准。 几十年来的疗法。免疫检查点抑制剂(ICIS)正在给癌症治疗带来革命性的变化，而肿瘤- 特定的新抗原是由此产生的强大的抗肿瘤T细胞反应的关键成分 探员们。新出现的临床数据显示，ICIS可显著延长半数MPM患者的生命 但与免疫相关的副作用有关。目前还没有可靠的生物标志物来识别MPM患者 世卫组织将对ICIS做出回应。这样的测试将避免不必要的毒性，将无反应者分流到可能更多的 有效的治疗，甚至可以延长长期生存。我们的初步数据显示，MPM肿瘤来自 对ICIS反应良好的患者具有1)明显的MPM细胞和组织构筑特征 独特的免疫环境，以及2)在多肽水平和 与其呈递给T细胞所需的特定的人类白细胞抗原蛋白同时表达。我们的 中心假说是MPM对PD-1阻断的反应可以通过临床适用的 其免疫组织的生物标记物和需要新的抗原：MHC一致性。在目标1中，我们将应用 飞行时间质谱仪(CyTOF)和成像质谱仪(IMC)的高维平台 剖析支配对nivolumab反应的MPM的细胞网络和免疫结构特征。 基于这些特征，我们得出了一个预测MPM对nivolumab反应的新评分，我们已经 开发了一个创新的生物信息学平台，从标准的福尔马林固定石蜡中提取这一分数- 嵌入(FFPE)临床组织切片。在目标1中，我们将优化并前瞻性地验证这一分数 MPM患者。在目标2中，我们将对HLA型肿瘤进行质谱仪(MS)的研究 新抗原生物学和挑战临床上用于预测新抗原负荷的主流生物标记物 在其他肿瘤中对ICIS的反应，但准确性较低。这个生物标记物完全依赖于新抗原。 在硅胶中预测，并不直接测量肿瘤中的新抗原。我们发现大量的MHC- MS检测MPM肿瘤中的I和MHC-II新抗原(称为新抗原丰度)与 对尼伏卢单抗敏感。更有趣的是，我们发现最有可能对MPM有反应的肿瘤 新抗原的多肽水平表达与特定人类白细胞抗原的高蛋白表达相一致 它们呈递所需的蛋白质(称为新抗原：MHC一致性)。这些新的指标将是 预期在AIM 2进行测试，在那里我们还将验证MS检测到的新抗原和 测定新抗原反应性T细胞的表型。我们的结果将定义 MPM的免疫蛋白质组结构和导致创新生物标记物的临床翻译有望 直接改善对MPM患者的护理。更广泛地说，这个项目的完成将推进我们的 了解人类癌症中新抗原生物学以及对ICIS的反应和耐药机制。

PROJECT SUMMARY / ABSTRACT Malignant pleural mesothelioma (MPM) is a fatal cancer of the lining of the lungs that has defeated standard therapies for decades. Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment, and tumor- specific neoantigens are critical components of the vigorous anti-tumor T cell responses possible from these agents. Emerging clinical data show that ICIs result in meaningful extension of life in half of patients with MPM but are associated with immune-related side effects. There is no reliable biomarker for identifying MPM patients who will respond to ICIs. Such a test would avoid unnecessary toxicity, triage non-responders to potentially more effective treatment, and could even extend long-term survival. Our preliminary data show that MPM tumors from patients that respond favorably to ICIs are rich in 1) distinct cellular and tissue architectural features of MPM's unique immune contexture, and 2) abundant tumor neoantigens that are detected at the peptide level and expressed concomitantly with the specific HLA proteins that are required for their presentation to T cells. Our central hypothesis is that response to PD-1 blockade in MPM can be predicted by a clinically-applicable biomarker of its immunologic organization and requires neoantigen:MHC concordance. In Aim 1, we will apply the high dimensional platforms of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry (IMC) to dissect the cellular networks and immuno-architectural features of MPM that govern response to nivolumab. Based on these features, we derived a novel score that predicts response to nivolumab in MPM and we have developed an innovative bioinformatics platform to abstract this score from standard formalin-fixed paraffin- embedded (FFPE) clinical tissue sections. In Aim 1, we will optimize and prospectively validate this score in patients with MPM. In Aim 2, we will perform mass spectrometry (MS) on HLA-typed tumors to investigate neoantigen biology and challenge the prevailing biomarker of neoantigen burden that is used clinically to predict response to ICIs in other tumors, but with low accuracy. This biomarker has relied exclusively on neoantigens predicted in silico and does not directly measure neoantigens in tumors. We found that high quantities of MHC- I and MHC-II neoantigens detected by MS in MPM tumors (termed neoantigen abundance) correlated with sensitivity to nivolumab. More interestingly, we found that the MPM tumors most likely to respond had high peptide level expression of neoantigens concordant with high protein level expression of the specific HLA proteins required for their presentation (termed neoantigen:MHC concordance). These novel metrics will be tested prospectively in Aim 2 where we will also validate the immunogenicity of MS-detected neoantigens and determine the phenotype of neoantigen-reactive T cells. Our results will define core elements of the immunoproteomic structure of MPM and result in the clinical translation of innovative biomarkers expected to directly improve the care of MPM patients. More broadly, completion of this project will advance our understanding of neoantigen biology and of mechanisms of response and resistance to ICIs in human cancer.