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

明确肿瘤内形态、免疫和突变异质性对尿路上皮细胞的影响 癌症 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 强化的多模式治疗，大约50%的肌肉侵袭性疾病患者发展为远处 从历史上看，这类患者长期存活的希望很小。免疫学的发展概况 检查点抑制剂是30年来膀胱癌治疗中最重要的进展， 这些药物的发展为许多以前无法治愈的转移患者带来了新的希望。 疾病。抗PD1/PD-L1抗体可在转移性膀胱患者中诱导持久的完全反应 带有几种免疫检查点抑制剂的癌症现在被FDA批准用于这一适应症。然而， 大多数转移性尿路上皮癌患者不能从免疫检查点阻断中受益，一些 最初有反应的患者后来会产生后天抵抗力。先天和后天的生物学基础 尿路上皮癌患者对免疫检查点阻断的抵抗力仍不明确。尿路上皮癌显示 在单个肿瘤中经常共存的各种形态的广泛范围。我们已经证明这一点 形态异质性通常与肿瘤内突变异质性有关。目前的提案 是基于初步数据，表明膀胱癌的形态异质性与 基因组和免疫的异质性，并预测对阿替唑珠单抗(一种抗PD-L1)的反应较差 抑制物)。提出了三个目标。在目标1中，我们将进行组织学、基因组学和免疫学的综合 从形态异质性肿瘤中分析成对、大体解剖、形态不同的区域 来自接受免疫检查点阻断治疗的患者，以确定肿瘤内的患病率和程度 遗传和免疫异质性。在目标2中，这些组织侧写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 确定对全身免疫治疗的反应。最后，在目标3中，我们将研究在 接受免疫检查点抑制剂治疗的患者的疾病进展情况确定是否存在预先存在的药物 耐药克隆存在于形态不同的原发肿瘤中，而且这些克隆较少 免疫原性癌细胞是慢性粒细胞白血病患者耐药和疾病进展的基础 形态不同的肿瘤。长期的翻译目标将是利用生物学的洞察 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 基于免疫的联合策略，可防止或延缓耐药克隆的出现。

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.