Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.
Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.
复制标题
非小细胞肺癌免疫检查点阻断过程中新抗原环境的演变。
DOI：
10.1158/2159-8290.cd-16-0828
复制
发表时间：
2017-03
期刊：
影响因子：
28.2
通讯作者：
Velculescu VE
中科院分区：
文献类型：
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作者：
Anagnostou V;Smith KN;Forde PM;Niknafs N;Bhattacharya R;White J;Zhang T;Adleff V;Phallen J;Wali N;Hruban C;Guthrie VB;Rodgers K;Naidoo J;Kang H;Sharfman W;Georgiades C;Verde F;Illei P;Li QK;Gabrielson E;Brock MV;Zahnow CA;Baylin SB;Scharpf RB;Brahmer JR;Karchin R;Pardoll DM;Velculescu VE
免疫检查点抑制剂已显示出对含有增加的突变相关新抗原负荷的肿瘤的显著治疗应答。我们已经检查了非小细胞肺癌患者在对使用抗PD 1或抗PD-1/抗CTLA 4抗体的免疫检查点阻断进行初始应答后出现获得性耐药期间肿瘤新抗原的演变情况。匹配的预处理和耐药肿瘤的分析确定了基因组变化，导致耐药克隆中7至18个推定的突变相关新抗原的丢失。从消除的新抗原产生的肽在自体T细胞培养物中引起克隆T细胞扩增，表明它们产生功能性免疫应答。通过消除肿瘤亚克隆或通过删除含有躯干改变的染色体区域发生新抗原丢失，并与T细胞受体克隆性的变化相关。这些分析为免疫检查点阻断期间突变景观的动态提供了见解，并对靶向肿瘤新抗原的免疫疗法的开发具有影响。
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in non-small cell lung cancer patients after initial response to immune checkpoint blockade with anti-PD1 or anti-PD-1/anti-CTLA4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T cell expansion in autologous T cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations and were associated with changes in T cell receptor clonality. These analyses provide insights into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for development of immune therapies that target tumor neoantigens.