Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.
Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.
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DOI：
10.1371/journal.pmed.1002309
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发表时间：
2017-05
期刊：
影响因子：
15.8
通讯作者：
Bajorin DF
中科院分区：
文献类型：
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作者：
Snyder A;Nathanson T;Funt SA;Ahuja A;Buros Novik J;Hellmann MD;Chang E;Aksoy BA;Al-Ahmadie H;Yusko E;Vignali M;Benzeno S;Boyd M;Moran M;Iyer G;Robins HS;Mardis ER;Merghoub T;Hammerbacher J;Rosenberg JE;Bajorin DF
用atezolizumab 抑制程序性死亡配体1 (PD-L1) 可以为转移性尿路上皮癌患者带来持久的临床获益(DCB)，包括化疗难治性疾病患者的完全缓解。尽管突变负荷和 PD-L1 免疫细胞 (IC) 染色与反应相关，但它们缺乏临床使用的足够敏感性和特异性。因此，需要评估外周血免疫环境，并对肿瘤中的突变负荷、预测的新抗原和免疫细胞浸润进行详细分析，以增强我们对反应和耐药的生物学基础的理解。本研究的目标是 (1) 评估突变负荷和预测的新抗原负荷与治疗益处的关联，以及 (2) 确定瘤内和外周血 T 细胞受体 (TCR) 克隆是否会影响阿特珠单抗治疗的尿路上皮癌的临床结果。我们假设，治疗前肿瘤内淋巴细胞或治疗后外周 T 细胞中突变负荷的升高与 T 细胞克隆优势相结合，与抗 PD-L1 治疗后肿瘤的有效控制相关。我们对治疗前的肿瘤样本进行了全外显子组测序 (WES)、RNA 测序 (RNA-seq) 和 T 细胞受体测序 (TCR-seq)，并对阿特朱单抗治疗前后收集的匹配、连续收集的外周血进行了 TCR-seq。评估这些参数与 DCB（定义为无进展生存期 [PFS] > 6 个月）、PFS 和总生存期 (OS) 的相关性，无论是单独使用还是结合已知可预测该疾病状态生存的临床和瘤内参数。 DCB 患者的肿瘤浸润性 T 淋巴细胞 (TIL) 比例较高（n = 24，Mann-Whitney p = 0.047）。治疗前外周血 TCR 克隆度低于中位数与改善 PFS（n = 29，对数秩 p = 0.048）和 OS（n = 29，对数秩 p = 0.011）相关。 DCB 患者在开始治疗 3 周后，外周血中肿瘤相关 TCR 克隆也表现出更大幅度的扩增（n = 22，Mann-Whitney p = 0.022）。治疗前外周血 TCR 克隆度高与肿瘤组织中 PD-L1 IC 染色升高的组合与不良临床结果密切相关（n = 10，风险比 (HR)（平均值）= 89.88，HR（中位数）= 23.41，95% CI [2.43, 506.94]，p(HR > 1) = 0.0014）。不同的体细胞变异检出方法观察到突变负荷的显着变化，这反过来又影响与临床结果的关联。错义突变负荷、预测的新抗原负荷和表达的新抗原负荷未显示与 DCB 显着相关（分别为 n = 25、Mann-Whitney p = 0.22、n = 25、Mann-Whitney p = 0.55 和 n = 25、Mann-Whitney p = 0.29）。相反，我们发现了体细胞突变负荷对该队列中 PFS 随时间变化影响的证据（n = 25，p = 0.044）。我们研究的一个局限性是样本量较小 (n = 29)，是接受 IMvigor 210 (NCT02108652) 治疗的患者的子集。考虑到所进行的探索性分析的数量，我们希望这些结果能够产生假设。这些结果证明了免疫反应对检查点封锁的复杂性，以及对宿主和肿瘤因子进行更多询问和数据整合的迫切需要。将这些变量纳入前瞻性研究将有助于识别和治疗耐药患者。 Alexandra Snyder 及其同事揭示了转移性尿路上皮癌患者对检查点阻断的免疫反应的复杂性。据报道，体细胞突变负荷对生存的随时间变化的影响。一种称为检查点封锁疗法的新型癌症治疗方法可以激活免疫系统来对抗癌症。当这些疗法发挥作用时，晚期疾病患者可以获得持久的疾病控制甚至治愈。然而，大多数患者不会体验到这些益处，因此提前识别这些患者至关重要，以便我们为他们开发更好的治疗方法。在这项研究中，我们研究了 29 名晚期膀胱癌患者，他们接受了名为 atezolizumab 的检查点阻断药物的治疗。我们检查了肿瘤和免疫系统的特征以及临床特征。我们发现这些特征以多种方式相互关联，并与治疗的成功相关。血液中含有多种 T 细胞的患者往往存活时间更长。临床预后因素较差的患者，例如癌症已转移至肝脏的患者，生存率往往较差。这项研究表明，如果我们要提高癌症免疫动员疗法的疗效，就需要考虑肿瘤、免疫系统和临床情况。一些患者可能病得太重，无法从检查点阻断疗法中获益，尽管在某些情况下，肿瘤中存在可以预测获益的生物标志物。
Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance. The goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially collected peripheral blood, collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state. Patients with DCB displayed a higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney p = 0.047). Pretreatment peripheral blood TCR clonality below the median was associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29, log-rank p = 0.011). Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1) = 0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which, in turn, impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load, and expressed neoantigen load did not demonstrate significant association with DCB (n = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25, Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A limitation of our study is its small sample size (n = 29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating. These results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients. Alexandra Snyder and colleagues reveal the complex nature of the immune response to checkpoint blockade in metastatic urothelial cancer patients. Time-varying effects of somatic mutation load on survival are reported. A new type of cancer treatment called checkpoint blockade therapy activates the immune system to fight cancer. When these therapies work, patients with advanced disease can experience long-lasting disease control or even cures. However, most patients will not experience these benefits, and it is crucial to identify these patients in advance so that we can develop better treatments for them. In this study, we studied 29 patients with advanced bladder cancers treated with a checkpoint blockade drug called atezolizumab. We examined features of the tumor and the immune system, as well as clinical features. We found that these features were related to each other, and to the success of therapy, in various ways. Patients who had a diverse repertoire of T cells in their blood tended to survive longer. Patients who had poor clinical prognostic factors, like having cancer that had traveled to their liver, tended to have worse survival. This study demonstrates that we need to take the tumor, immune system, and clinical picture into account if we are to improve the efficacy of immune-mobilizing therapies in cancer. Some patients may be too sick to benefit from checkpoint blockade therapy, despite, in some cases, having biomarkers in their tumors that would predict benefit.