Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

明确肿瘤内形态学、免疫和突变异质性对尿路上皮细胞的影响 癌 膀胱癌是全球第九大常见癌症，也是男性第四大常见癌症。尽管 在强化的多模态治疗中，大约50%的肌肉浸润性疾病患者发生远处转移， 转移和历史上这样的患者几乎没有长期生存的希望。免疫的发展 检查点抑制剂是三十年来膀胱癌最重要的治疗进展， 这些药物的开发为许多以前无法治愈的转移性癌患者提供了新的希望。 疾病抗PD 1/PD-L1抗体可在转移性膀胱癌患者中诱导持久的完全缓解 具有几种免疫检查点抑制剂的癌症现在被FDA批准用于该适应症。但 大多数转移性尿路上皮癌患者不能从免疫检查点阻断中获益， 最初有反应的患者后来发展为获得性耐药。先天和后天的生物学基础 尿路上皮癌对免疫检查点阻断的抗性仍然不明确。尿路上皮癌显示 一个广泛的变异形态，往往共存于个别肿瘤。我们已经证明， 形态异质性通常与肿瘤内突变异质性相关。现时的建议 基于初步数据，表明膀胱癌的形态异质性与 基因组和免疫异质性，并预测对atezolizumab（抗PD-L1抗体）的反应较差 抑制剂）。提出了三个目标。在目标1中，我们将进行整合的组织学，基因组学和免疫学研究， 对形态异质性肿瘤的成对、宏观解剖、形态不同区域的分析 来自接受免疫检查点阻断治疗的患者，以确定肿瘤内 遗传和免疫异质性。在目标2中，这些组织分析研究将与详细的临床研究相结合。 和患者反应数据，以确定预先存在的组织学、基因组和免疫异质性在 确定对全身免疫疗法的反应。最后，在目标3中，我们将研究在研究时收集的肿瘤。 接受免疫检查点抑制剂治疗的患者的疾病进展，以确定是否存在既存药物 耐药克隆存在于形态异质性原发性肿瘤中， 免疫原性癌细胞是患者耐药性和疾病进展的基础 形态异质性肿瘤。长期的转化目标将是利用生物学的见解 获得了开发改进的免疫治疗敏感性和耐药性的生物标志物，并开发合理的 基于免疫的组合策略，预防或延迟耐药克隆的出现。

Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma Bladder cancer is the ninth most common cancer worldwide and the fourth most common cancer in men. Despite intensive multi-modality therapy, approximately 50% of patients with muscle-invasive disease develop distant metastases and historically such patients had little hope of long-term survival. The development of immune checkpoint inhibitors is the most significant therapeutic advance in bladder cancer in three decades and the development of these agents have provided renewed hope to many patients with previously incurable metastatic disease. Anti-PD1/PD-L1 antibodies can induce durable complete responses in patients with metastatic bladder cancer with several immune checkpoint inhibitors are now FDA-approved for this indication. However, the majority of patients with metastatic urothelial cancers do not benefit from immune checkpoint blockade and some patients who initially respond later develop acquired resistance. The biologic basis for innate and acquired resistance to immune checkpoint blockade in urothelial cancer remains poorly defined. Urothelial cancers display a wide spectrum of variant morphologies that often co-exist within individual tumors. We have shown that this morphologic heterogeneity is often associated with intra-tumoral mutational heterogeneity. The current proposal is based upon preliminary data indicating that morphologic heterogeneity in bladder cancer is associated with genomic and immune heterogeneity and is predictive of a worse response to atezolizumab (an anti-PD-L1 inhibitor). Three aims are proposed. In Aim 1, we will perform integrated histologic, genomic and immune analyses of paired, macro-dissected, morphologically distinct areas from morphologically heterogeneous tumors from patients treated with immune checkpoint blockade to define the prevalence and extent of intratumoral genetic and immune heterogeneity. In Aim 2, these tissue profiling studies will be integrated with detailed clinical and patients response data to define the role of pre-existent histologic, genomic and immune heterogeneity in determining response to systemic immunotherapy. Finally, in Aim 3, we will study tumors collected at the time of disease progression in patients treated with immune checkpoint inhibitors to determine whether pre-existent drug resistant clones were present in morphologically heterogeneous primary tumors and that these less immunogenic cancer cells are a basis for drug resistance and disease progression in patients with morphologically heterogeneous tumors. The long-term translational objective will be to use the biologic insights gained to develop improved biomarkers of immunotherapy sensitivity and resistance, and to develop rational immune-based combination strategies that prevent or delay the emergence of drug resistant clones.