Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages

被引：423

作者：

Bohn, Toszka ^{[1
]}

Rapp, Steffen ^{[2
]}

Luther, Natascha ^{[3
]}

Klein, Matthias ^{[1
]}

Bruehl, Till-Julius ^{[1
]}

Kojima, Nobuhiko ^{[4
]}

Lopez, Pamela Aranda ^{[5
]}

Hahlbrock, Jennifer ^{[1
]}

Muth, Sabine ^{[1
]}

Endo, Shogo ^{[6
]}

Pektor, Stefanie ^{[7
]}

Brand, Almut ^{[8
]}

Renner, Kathrin ^{[8
,9
]}

Popp, Vanessa ^{[10
]}

Gerlach, Katharina ^{[10
]}

Vogel, Dennis ^{[11
,12
]}

Lueckel, Christina ^{[1
,11
,12
]}

Arnold-Schild, Danielle ^{[1
]}

Pouyssegur, Jacques ^{[13
,14
]}

Kreutz, Marina ^{[8
,9
]}

Huber, Magdalena ^{[11
,12
]}

Koenig, Jochem ^{[15
]}

Weigmann, Benno ^{[10
]}

Probst, Hans-Christian ^{[1
,16
]}

von Stebut, Esther ^{[17
]}

Becker, Christian ^{[3
,14
,16
]}

Schild, Hansjoerg ^{[1
,16
,18
]}

Schmitt, Edgar ^{[1
,16
]}

Bopp, Tobias ^{[1
,16
,18
,19
]}

机构：

[1] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Immunol, Mainz, Germany

[2] Johannes Gutenberg Univ Mainz, Mol Genet, Mainz, Germany

[3] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dermatol, Mainz, Germany

[4] Toyo Univ, Fac Life Sci, Gunma, Japan

[5] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Med Clin 3, Mainz, Germany

[6] Tokyo Metropolitan Inst Gerontol, Aging Neurosci Res Team, Tokyo, Japan

[7] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Nucl Med, Mainz, Germany

[8] Univ Regensburg, Internal Med 3, Regensburg, Germany

[9] RCI, Regensburg, Germany

[10] Univ Erlangen Nurnberg, Dept Med 1, Erlangen, Germany

[11] Univ Marburg, Inst Med Microbiol, Marburg, Germany

[12] Univ Marburg, Hosp Hyg, Marburg, Germany

[13] Univ Nice Sophia Antipolis, Inst Res Canc & Aging, Nice, France

[14] CSM, Med Biol Dept, Monaco, Monaco

[15] Johannes Gutenberg Univ Mainz, Univ Med Ctr, IMBEI, Mainz, Germany

[16] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Res Ctr Immunotherapy FZI, Mainz, Germany

[17] Univ Med Ctr Cologne, Dermatol & Venereol, Cologne, Germany

[18] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Univ Canc Ctr, Mainz, Germany

[19] German Canc Consortium DKTK, Heidelberg, Germany

来源：

NATURE IMMUNOLOGY | 2018年 / 19卷 / 12期

关键词：

SERUM LACTATE-DEHYDROGENASE; PROTEIN-COUPLED RECEPTORS; CAMP EARLY REPRESSOR; NF-KAPPA-B; LACTIC-ACID; INFLAMMATORY RESPONSES; SOLID TUMORS; IN-VITRO; IMMUNE; PROGRESSION;

D O I：

10.1038/s41590-018-0226-8

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.

引用

页码：1319 / +

页数：14

共 51 条

[1]

[Anonymous], 2017, Miscellaneous functions for Grid Graphics R package gridExtra version 2.3

[2]

Final Version of 2009 AJCC Melanoma Staging and Classification [J].

Balch, Charles M. ;

Gershenwald, Jeffrey E. ;

Soong, Seng-jaw ;

Thompson, John F. ;

Atkins, Michael B. ;

Byrd, David R. ;

Buzaid, Antonio C. ;

Cochran, Alistair J. ;

Coit, Daniel G. ;

Ding, Shouluan ;

Eggermont, Alexander M. ;

Flaherty, Keith T. ;

Gimotty, Phyllis A. ;

Kirkwood, John M. ;

McMasters, Kelly M. ;

Mihm, Martin C., Jr. ;

Morton, Donald L. ;

Ross, Merrick I. ;

Sober, Arthur J. ;

Sondak, Vernon K. .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (36) :6199-6206

[3]

In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy [J].

Becker, C ;

Fantini, MC ;

Wirtz, S ;

Nikolaev, A ;

Kiesslich, R ;

Lehr, HA ;

Galle, PR ;

Neurath, MF .

GUT, 2005, 54 (07) :950-954

[4]

A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation) [J].

Biswas, SK ;

Gangi, L ;

Paul, S ;

Schioppa, T ;

Saccani, A ;

Sironi, M ;

Bottazzi, B ;

Doni, A ;

Vincenzo, B ;

Pasqualini, F ;

Vago, L ;

Nebuloni, M ;

Mantovani, A ;

Sica, A .

BLOOD, 2006, 107 (05) :2112-2122

[5]

LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells [J].

Brand, Almut ;

Singer, Katrin ;

Koehl, Gudrun E. ;

Kolitzus, Marlene ;

Schoenhammer, Gabriele ;

Thiel, Annette ;

Matos, Carina ;

Bruss, Christina ;

Klobuch, Sebastian ;

Peter, Katrin ;

Kastenberger, Michael ;

Bogdan, Christian ;

Schleicher, Ulrike ;

Mackensen, Andreas ;

Ullrich, Evelyn ;

Fichtner-Feigl, Stefan ;

Kesselring, Rebecca ;

Mack, Matthias ;

Ritter, Uwe ;

Schmid, Maximilian ;

Blank, Christian ;

Dettmer, Katja ;

Oefner, Peter J. ;

Hoffmann, Petra ;

Walenta, Stefan ;

Geissler, Edward K. ;

Pouyssegur, Jacques ;

Villunger, Andreas ;

Steven, Andre ;

Seliger, Barbara ;

Schreml, Stephan ;

Haferkamp, Sebastian ;

Kohl, Elisabeth ;

Karrer, Sigrid ;

Berneburg, Mark ;

Herr, Wolfgang ;

Mueller-Klieser, Wolfgang ;

Renner, Kathrin ;

Kreutz, Marina .

Cell Metabolism, 2016, 24 (05) :657-671

[6]

Metabolic origins of spatial organization in the tumor microenvironment [J].

Carmona-Fontaine, Carlos ;

Deforet, Maxime ;

Akkari, Leila ;

Thompson, Craig B. ;

Joyce, Johanna A. ;

Xavier, Joao B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (11) :2934-2939

[7]

The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth [J].

Christofk, Heather R. ;

Vander Heiden, Matthew G. ;

Harris, Marian H. ;

Ramanathan, Arvind ;

Gerszten, Robert E. ;

Wei, Ru ;

Fleming, Mark D. ;

Schreiber, Stuart L. ;

Cantley, Lewis C. .

NATURE, 2008, 452 (7184) :230-U74

[8]

Conditional gene targeting in macrophages and granulocytes using LysMcre mice [J].

Clausen, BE ;

Burkhardt, C ;

Reith, W ;

Renkawitz, R ;

Förster, I .

TRANSGENIC RESEARCH, 1999, 8 (04) :265-277

[9]

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid [J].

Colegio, Oscar R. ;

Ngoc-Quynh Chu ;

Szabo, Alison L. ;

Chu, Thach ;

Rhebergen, Anne Marie ;

Jairam, Vikram ;

Cyrus, Nika ;

Brokowski, Carolyn E. ;

Eisenbarth, Stephanie C. ;

Phillips, Gillian M. ;

Cline, Gary W. ;

Phillips, Andrew J. ;

Medzhitov, Ruslan .

NATURE, 2014, 513 (7519) :559-+

[10]

Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane [J].

Damaghi, Mehdi ;

Tafreshi, Narges K. ;

Lloyd, Mark C. ;

Sprung, Robert ;

Estrella, Veronica ;

Wojtkowiak, Jonathan W. ;

Morse, David L. ;

Koomen, John M. ;

Bui, Marilyn M. ;

Gatenby, Robert A. ;

Gillies, Robert J. .

NATURE COMMUNICATIONS, 2015, 6

← 1 2 3 4 5 6 →