Immunogenomic profile of colorectal cancer response to immune checkpoint blockade
Immunogenomic profile of colorectal cancer response to immune checkpoint blockade
复制标题
结直肠癌对免疫检查点封锁反应的免疫基因组学特征
DOI：
10.1101/2020.12.15.422831
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Bortolomeazzi M
中科院分区：
文献类型：
--
作者：
Bortolomeazzi M
结直肠癌（CRC）对免疫检查点阻断表现出可变的反应，这只能部分地由肿瘤突变负荷的可变性来解释。为了剖析反应的细胞和分子决定因素，我们对来自用Pembrolizumab（KEYNOTE 177临床试验）或Nivolumab治疗的患者的721个癌症区域进行了多组学筛选。多区域全外显子组、RNA和T细胞受体测序表明，在高度突变的CRC中，对两种抗PD 1药物的应答与肿瘤突变负荷不呈正相关，但与免疫原性突变的高克隆性、扩增的T细胞、WNT途径的低活化和主动免疫逃逸机制相关。将高维成像质谱细胞术与多重免疫荧光和计算空间分析相结合，我们观察到响应性超突变的CRC富含细胞毒性和增殖性PD 1表达CD 8细胞，这些细胞与高密度聚簇的PDL 1表达抗原呈递巨噬细胞相互作用。我们提出，抗PD 1药物释放CD 8 T细胞和巨噬细胞之间的PD 1-PDL 1相互作用，从而促进细胞毒性抗肿瘤活性。
Colorectal cancers (CRCs) show variable response to immune checkpoint blockade, which can only partially be explained by the variability of tumour mutational burden. To dissect the cellular and molecular determinants of response we performed a multi-omic screen of 721 cancer regions from patients treated with Pembrolizumab (KEYNOTE 177 clinical trial) or Nivolumab. Multi-regional whole exome, RNA and T-cell receptor sequencing show that, within hypermutated CRCs, response to both anti-PD1 agents is not positively associated with tumour mutational burden but with high clonality of immunogenic mutations, expanded T cells, low activation of the WNT pathway and active immune escape mechanisms. Coupling high-dimensional imaging mass cytometry with multiplexed immunofluorescence and computational spatial analysis, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 cells interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting cytotoxic anti-tumour activity.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
48
作者：
Berg, Stuart;Kutra, Dominik;Kreshuk, Anna
通讯作者：
Kreshuk, Anna
影响因子：
7
作者：
McKenna, Aaron;Hanna, Matthew;DePristo, Mark A.
通讯作者：
DePristo, Mark A.
肿瘤中的PD-1封锁不匹配缺陷。
DOI：
10.1056/nejmoa1500596
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Le DT;Uram JN;Wang H;Bartlett BR;Kemberling H;Eyring AD;Skora AD;Luber BS;Azad NS;Laheru D;Biedrzycki B;Donehower RC;Zaheer A;Fisher GA;Crocenzi TS;Lee JJ;Duffy SM;Goldberg RM;de la Chapelle A;Koshiji M;Bhaijee F;Huebner T;Hruban RH;Wood LD;Cuka N;Pardoll DM;Papadopoulos N;Kinzler KW;Zhou S;Cornish TC;Taube JM;Anders RA;Eshleman JR;Vogelstein B;Diaz LA Jr
通讯作者：
Diaz LA Jr
影响因子：
50.3
作者：
Yaeger R;Chatila WK;Lipsyc MD;Hechtman JF;Cercek A;Sanchez-Vega F;Jayakumaran G;Middha S;Zehir A;Donoghue MTA;You D;Viale A;Kemeny N;Segal NH;Stadler ZK;Varghese AM;Kundra R;Gao J;Syed A;Hyman DM;Vakiani E;Rosen N;Taylor BS;Ladanyi M;Berger MF;Solit DB;Shia J;Saltz L;Schultz N
通讯作者：
Schultz N