Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
复制标题
DOI：
10.1158/2159-8290.cd-15-1545
复制
发表时间：
2016-08
期刊：
影响因子：
28.2
通讯作者：
Wargo JA
中科院分区：
文献类型：
--
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
免疫检查点阻断代表着癌症治疗的重大突破，但反应并不是通用的。据报道，治疗前肿瘤活检中的基因组和免疫特征与黑色素瘤和其他癌症患者的反应相关，但尚未确定强有力的生物标志物。我们研究了一组转移性黑色素瘤患者，最初接受细胞毒性T淋巴细胞相关抗原-4(CTLA-4)阻断(n=53)，然后进行程序性死亡-1(PD-1)阻断(n=46)，并分析了治疗期间多个时间点收集的纵向组织样本的免疫特征。在这些研究中，我们证明了在治疗过程中早期获得的肿瘤活检样本中的获得性免疫信号可以很好地预测免疫检查点阻断的反应，并且还显示了CTLA-4和PD-1阻断对肿瘤微环境的不同影响。重要的是，治疗抵抗免疫检查点阻断的潜在机制也被确定。这些研究表明，早期接受治疗的肿瘤活检组织中的获得性免疫信号可以预测对检查点阻断的反应，并有助于深入了解治疗耐药的机制。这些概念在这个精准医学时代具有深远的影响，应该在跨癌症类型的免疫检查点阻断治疗中进行探索。
Immune checkpoint blockade represents a major breakthrough in cancer therapy, however responses are not universal. Genomic and immune features in pre-treatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of metastatic melanoma patients initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade (n=53) followed by programmed death-1 (PD-1) blockade at progression (n=46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In these studies, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade, and also demonstrate differential effects on the tumor microenvironment induced by CTLA-4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade, and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine, and should be explored in immune checkpoint blockade treatment across cancer types.