Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer

被引：345

作者：

Jia, Qingzhu ^{[1
,2
]}

Wu, Wei ^{[3
]}

Wang, Yuqi ^{[4
]}

Alexander, Peter B. ^{[5
]}

Sun, Chengdu ^{[1
,2
]}

Gong, Zhihua ^{[1
,2
]}

Cheng, Jia-Nan ^{[1
,2
,6
]}

Sun, Huaibo ^{[4
]}

Guan, Yanfang ^{[4
]}

Xia, Xuefeng ^{[4
,7
]}

Yang, Ling ^{[4
]}

Yi, Xin ^{[4
]}

Wan, Yisong Y. ^{[8
]}

Wang, Haidong ^{[3
]}

He, Ji ^{[9
]}

Futreal, P. Andrew ^{[10
]}

Li, Qi-Jing ^{[5
,6
]}

Zhu, Bo ^{[1
,2
]}

机构：

[1] Third Mil Med Univ, Xinqiao Hosp, Inst Canc, Chongqing 400037, Peoples R China

[2] Chongqing Key Lab Tumor Immunotherapy, Chongqing 400037, Peoples R China

[3] Third Mil Med Univ, Southwest Hosp, Dept Cardiothorath Surg, Chongqing 400038, Peoples R China

[4] Geneplus Beijing Inst, Beijing 102206, Peoples R China

[5] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA

[6] Third Mil Med Univ, Biomed Anal Ctr, Chongqing 400038, Peoples R China

[7] Houston Methodist Res Inst, Houston, TX 77030 USA

[8] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Microbiol & Immunol, Chapel Hill, NC 27514 USA

[9] GeneCast Biotechnol Co Ltd, Beijing 102206, Peoples R China

[10] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

PD-1; BLOCKADE; CTLA-4; OPEN-LABEL; NIVOLUMAB; EVOLUTION; DOCETAXEL; MULTICENTER; TUMORS; ADENOCARCINOMA; ATEZOLIZUMAB;

D O I：

10.1038/s41467-018-07767-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance. Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy.

引用

页数：10

共 58 条

[1] Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy [J].

Angelova, Mihaela ;

Charoentong, Pornpimol ;

Hackl, Hubert ;

Fischer, Maria L. ;

Snajder, Rene ;

Krogsdam, Anne M. ;

Waldner, Maximilian J. ;

Bindea, Gabriela ;

Mlecnik, Bernhard ;

Galon, Jerome ;

Trajanoski, Zlatko .

GENOME BIOLOGY, 2015, 16

[2] Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer [J].

Balachandran, Vinod P. ;

Luksza, Marta ;

Zhao, Julia N. ;

Makarov, Vladimir ;

Moral, John Alec ;

Remark, Romain ;

Herbst, Brian ;

Askan, Gokce ;

Bhanot, Umesh ;

Senbabaoglu, Yasin ;

Wells, Daniel K. ;

Cary, Charles Ian Ormsby ;

Grbovic-Huezo, Olivera ;

Attiyeh, Marc ;

Medina, Benjamin ;

Zhang, Jennifer ;

Loo, Jennifer ;

Saglimbeni, Joseph ;

Abu-Akeel, Mohsen ;

Zappasodi, Roberta ;

Riaz, Nadeem ;

Smoragiewicz, Martin ;

Kelley, Z. Larkin ;

Basturk, Olca ;

Goenen, Mithat ;

Levine, Arnold J. ;

Allen, Peter J. ;

Fearon, Douglas T. ;

Merad, Miriam ;

Gnjatic, Sacha ;

Iacobuzio-Donahue, Christine A. ;

Wolchok, Jedd D. ;

DeMatteo, Ronald P. ;

Chan, Timothy A. ;

Greenbaum, Benjamin D. ;

Merghoub, Taha ;

Leach, Steven D. .

NATURE, 2017, 551 (7681) :512-+

[3] Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].

Barbie, David A. ;

Tamayo, Pablo ;

Boehm, Jesse S. ;

Kim, So Young ;

Moody, Susan E. ;

Dunn, Ian F. ;

Schinzel, Anna C. ;

Sandy, Peter ;

Meylan, Etienne ;

Scholl, Claudia ;

Froehling, Stefan ;

Chan, Edmond M. ;

Sos, Martin L. ;

Michel, Kathrin ;

Mermel, Craig ;

Silver, Serena J. ;

Weir, Barbara A. ;

Reiling, Jan H. ;

Sheng, Qing ;

Gupta, Piyush B. ;

Wadlow, Raymond C. ;

Le, Hanh ;

Hoersch, Sebastian ;

Wittner, Ben S. ;

Ramaswamy, Sridhar ;

Livingston, David M. ;

Sabatini, David M. ;

Meyerson, Matthew ;

Thomas, Roman K. ;

Lander, Eric S. ;

Mesirov, Jill P. ;

Root, David E. ;

Gilliland, D. Gary ;

Jacks, Tyler ;

Hahn, William C. .

NATURE, 2009, 462 (7269) :108-U122

[4] Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers [J].

Blakely, Collin M. ;

Watkins, Thomas B. K. ;

Wu, Wei ;

Gini, Beatrice ;

Chabon, Jacob J. ;

McCoach, Caroline E. ;

McGranahan, Nicholas ;

Wilson, Gareth A. ;

Birkbak, Nicolai J. ;

Olivas, Victor R. ;

Rotow, Julia ;

Maynard, Ashley ;

Wang, Victoria ;

Gubens, Matthew A. ;

Banks, Kimberly C. ;

Lanman, Richard B. ;

Caulin, Aleah F. ;

St John, John ;

Cordero, Anibal R. ;

Giannikopoulos, Petros ;

Simmons, Andrew D. ;

Mack, Philip C. ;

Gandara, David R. ;

Husain, Hatim ;

Doebele, Robert C. ;

Riess, Jonathan W. ;

Diehn, Maximilian ;

Swanton, Charles ;

Bivona, Trever G. .

NATURE GENETICS, 2017, 49 (12) :1693-+

[5] The determinants of tumour immunogenicity [J].

Blankenstein, Thomas ;

Coulie, Pierre G. ;

Gilboa, Eli ;

Jaffee, Elizabeth M. .

NATURE REVIEWS CANCER, 2012, 12 (04) :307-313

[6] MiXCR: software for comprehensive adaptive immunity profiling [J].

Bolotin, Dmitriy A. ;

Poslavsky, Stanislav ;

Mitrophanov, Igor ;

Shugay, Mikhail ;

Mamedov, Ilgar Z. ;

Putintseva, Ekaterina V. ;

Chudakov, Dmitriy M. .

NATURE METHODS, 2015, 12 (05) :380-381

[7] Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer [J].

Borghaei, H. ;

Paz-Ares, L. ;

Horn, L. ;

Spigel, D. R. ;

Steins, M. ;

Ready, N. E. ;

Chow, L. Q. ;

Vokes, E. E. ;

Felip, E. ;

Holgado, E. ;

Barlesi, F. ;

Kohlhaeufl, M. ;

Arrieta, O. ;

Burgio, M. A. ;

Fayette, J. ;

Lena, H. ;

Poddubskaya, E. ;

Gerber, D. E. ;

Gettinger, S. N. ;

Rudin, C. M. ;

Rizvi, N. ;

Crino, L. ;

Blumenschein, G. R. ;

Antonia, S. J. ;

Dorange, C. ;

Harbison, C. T. ;

Finckenstein, F. Graf ;

Brahmer, J. R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (17) :1627-1639

[8] Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer [J].

Brahmer, Julie ;

Reckamp, Karen L. ;

Baas, Paul ;

Crino, Lucio ;

Eberhardt, Wilfried E. E. ;

Poddubskaya, Elena ;

Antonia, Scott ;

Pluzanski, Adam ;

Vokes, Everett E. ;

Holgado, Esther ;

Waterhouse, David ;

Ready, Neal ;

Gainor, Justin ;

Aren Frontera, Osvaldo ;

Havel, Libor ;

Steins, Martin ;

Garassino, Marina C. ;

Aerts, Joachim G. ;

Domine, Manuel ;

Paz-Ares, Luis ;

Reck, Martin ;

Baudelet, Christine ;

Harbison, Christopher T. ;

Lestini, Brian ;

Spigel, David R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (02) :123-135

[9] First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer [J].

Carbone, D. P. ;

Reck, M. ;

Paz-Ares, L. ;

Creelan, B. ;

Horn, L. ;

Steins, M. ;

Felip, E. ;

van den Heuvel, M. M. ;

Ciuleanu, T. -E. ;

Badin, F. ;

Ready, N. ;

Hiltermann, T. J. N. ;

Nair, S. ;

Juergens, R. ;

Peters, S. ;

Minenza, E. ;

Wrangle, J. M. ;

Rodriguez-Abreu, D. ;

Borghaei, H. ;

Blumenschein, G. R. ;

Villaruz, L. C. ;

Havel, L. ;

Krejci, J. ;

Corral Jaime, J. ;

Chang, H. ;

Geese, W. J. ;

Bhagavatheeswaran, P. ;

Chen, A. C. ;

Socinski, M. A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (25) :2415-2426

[10] Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade [J].

Charoentong, Pornpimol ;

Finotello, Francesca ;

Angelova, Mihaela ;

Mayer, Clemens ;

Efremova, Mirjana ;

Rieder, Dietmar ;

Hackl, Hubert ;

Trajanoski, Zlatko .

CELL REPORTS, 2017, 18 (01) :248-262

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