LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells

被引：1762

作者：

Brand, Almut ^{[1
]}

Singer, Katrin ^{[1
]}

Koehl, Gudrun E. ^{[2
]}

Kolitzus, Marlene ^{[1
]}

Schoenhammer, Gabriele ^{[1
]}

Thiel, Annette ^{[1
]}

Matos, Carina ^{[1
]}

Bruss, Christina ^{[1
]}

Klobuch, Sebastian ^{[1
]}

Peter, Katrin ^{[1
,3
]}

Kastenberger, Michael ^{[1
]}

Bogdan, Christian ^{[4
]}

Schleicher, Ulrike ^{[4
]}

Mackensen, Andreas ^{[5
]}

Ullrich, Evelyn ^{[5
,6
]}

Fichtner-Feigl, Stefan ^{[2
,3
]}

Kesselring, Rebecca ^{[2
]}

Mack, Matthias ^{[3
,7
]}

Ritter, Uwe ^{[8
]}

Schmid, Maximilian ^{[1
,8
]}

Blank, Christian ^{[9
]}

Dettmer, Katja ^{[10
]}

Oefner, Peter J. ^{[10
]}

Hoffmann, Petra ^{[1
,3
]}

Walenta, Stefan ^{[11
]}

Geissler, Edward K. ^{[2
]}

Pouyssegur, Jacques ^{[12
,13
]}

Villunger, Andreas ^{[14
,15
]}

Steven, Andre ^{[16
]}

Seliger, Barbara ^{[16
]}

Schreml, Stephan ^{[17
]}

Haferkamp, Sebastian ^{[17
]}

Kohl, Elisabeth ^{[17
]}

Karrer, Sigrid ^{[17
]}

Berneburg, Mark ^{[17
]}

Herr, Wolfgang ^{[1
]}

Mueller-Klieser, Wolfgang ^{[11
]}

Renner, Kathrin ^{[1
,3
]}

Kreutz, Marina ^{[1
,3
]}

机构：

[1] Univ Hosp Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany

[2] Univ Hosp Regensburg, Dept Surg, D-93053 Regensburg, Germany

[3] Univ Regensburg, Regensburg Ctr Intervent Immunol, D-93053 Regensburg, Germany

[4] Friedrich Alexander Univ FAU Erlangen Nurnberg, Univ Klinikum Erlangen, Mikrobiol Inst Klin Mikrobiol Immunol & Hyg, D-91054 Erlangen, Germany

[5] Univ Hosp Erlangen, Dept Internal Med 5, Hematol Oncol, D-91054 Erlangen, Germany

[6] Goethe Univ, Univ Hosp Frankfurt, Dept Children & Adolescents Med, Cellular Immunol Pediat Stem Cell Transplantat &, D-60590 Frankfurt, Germany

[7] Univ Hosp Regensburg, Dept Internal Med Nephrol 2, D-93053 Regensburg, Germany

[8] Univ Regensburg, Inst Immunol, D-93053 Regensburg, Germany

[9] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands

[10] Univ Regensburg, Inst Funct Genom, D-93053 Regensburg, Germany

[11] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Pathophysiol, D-55128 Mainz, Germany

[12] Univ Nice Sophia Antipolis, Inst Res Canc & Aging, Ctr A Lacassagne, F-06189 Nice, France

[13] Ctr Sci Monaco CSM, MC-98000 Monaco, Monaco

[14] Med Univ Innsbruck, Div Dev Immunol, Bioctr, A-6020 Innsbruck, Austria

[15] Tyrolean Canc Res Inst, A-6020 Innsbruck, Austria

[16] Martin Luther Univ Halle Wittenberg, Inst Med Immunol Halle Saale, D-06112 Halle, Germany

[17] Univ Hosp Regensburg, Dept Dermatol, D-93053 Regensburg, Germany

来源：

Cell Metabolism | 2016年 / 24卷 / 05期

关键词：

LACTATE-DEHYDROGENASE; METASTATIC MELANOMA; INTERFERON-GAMMA; PATIENT SURVIVAL; IMMUNE CELLS; GLYCOLYSIS; CANCER; MICROENVIRONMENT; PROGRESSION; REJECTION;

D O I：

10.1016/j.cmet.2016.08.011

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-gamma-producing T and NK cells. However, in Rag2(-/-)gamma c(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-gamma production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.

引用

页码：657 / 671

页数：15

共 36 条

[1]

B Cells Regulate Macrophage Phenotype and Response to Chemotherapy in Squamous Carcinomas [J].

Affara, Nesrine I. ;

Ruffell, Brian ;

Medler, Terry R. ;

Gunderson, Andrew J. ;

Johansson, Magnus ;

Bornstein, Sophia ;

Bergsland, Emily ;

Steinhoff, Martin ;

Li, Yijin ;

Gong, Qian ;

Ma, Yan ;

Wiesen, Jane F. ;

Wong, Melissa H. ;

Kulesz-Martin, Molly ;

Irving, Bryan ;

Coussens, Lisa M. .

CANCER CELL, 2014, 25 (06) :809-821

[2]

PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells [J].

Blank, C ;

Brown, I ;

Peterson, AC ;

Spiotto, M ;

Iwai, Y ;

Honjo, T ;

Gajewski, TF .

CANCER RESEARCH, 2004, 64 (03) :1140-1145

[3]

Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival [J].

Bogunovic, Dusan ;

O'Neill, David W. ;

Belitskaya-Levy, Ilana ;

Vacic, Vladimir ;

Yu, Yi-Lo ;

Adams, Sylvia ;

Darvishian, Farbod ;

Berman, Russell ;

Shapiro, Richard ;

Pavlick, Anna C. ;

Lonardi, Stefano ;

Zavadil, Jiri ;

Osman, Iman ;

Bhardwaj, Nina .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (48) :20429-20434

[4]

Modulation of Microenvironment Acidity Reverses Anergy in Human and Murine Tumor-Infiltrating T Lymphocytes [J].

Calcinotto, Arianna ;

Filipazzi, Paola ;

Grioni, Matteo ;

Iero, Manuela ;

De Milito, Angelo ;

Ricupito, Alessia ;

Cova, Agata ;

Canese, Rossella ;

Jachetti, Elena ;

Rossetti, Monica ;

Huber, Veronica ;

Parmiani, Giorgio ;

Generoso, Luca ;

Santinami, Mario ;

Borghi, Martina ;

Fais, Stefano ;

Bellone, Matteo ;

Rivoltini, Licia .

CANCER RESEARCH, 2012, 72 (11) :2746-2756

[5]

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression [J].

Chang, Chih-Hao ;

Qiu, Jing ;

O'Sullivan, David ;

Buck, Michael D. ;

Noguchi, Takuro ;

Curtis, Jonathan D. ;

Chen, Qiongyu ;

Gindin, Mariel ;

Gubin, Matthew M. ;

van der Windt, Gerritje J. W. ;

Tonc, Elena ;

Schreiber, Robert D. ;

Pearce, Edward J. ;

Pearce, Erika L. .

CELL, 2015, 162 (06) :1229-1241

[6]

Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis [J].

Chang, Chih-Hao ;

Curtis, Jonathan D. ;

Maggi, Leonard B., Jr. ;

Faubert, Brandon ;

Villarino, Alejandro V. ;

O'Sullivan, David ;

Huang, Stanley Ching-Cheng ;

van der Windt, Gerritje J. W. ;

Blagih, Julianna ;

Qiu, Jing ;

Weber, Jason D. ;

Pearce, Edward J. ;

Jones, Russell G. ;

Pearce, Erika L. .

CELL, 2013, 153 (06) :1239-1251

[7]

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-+

[8]

Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma [J].

Diem, S. ;

Kasenda, B. ;

Spain, L. ;

Martin-Liberal, J. ;

Marconcini, R. ;

Gore, M. ;

Larkin, J. .

BRITISH JOURNAL OF CANCER, 2016, 114 (03) :256-261

[9]

Lactic Acid and Acidification Inhibit TNF Secretion and Glycolysis of Human Monocytes [J].

Dietl, Katrin ;

Renner, Kathrin ;

Dettmer, Katja ;

Timischl, Birgit ;

Eberhart, Karin ;

Dorn, Christoph ;

Hellerbrand, Claus ;

Kastenberger, Michael ;

Kunz-Schughart, Leoni A. ;

Oefner, Peter J. ;

Andreesen, Reinhard ;

Gottfried, Eva ;

Kreutz, Marina P. .

JOURNAL OF IMMUNOLOGY, 2010, 184 (03) :1200-1209

[10]

REGULATION OF T-CELL FUNCTIONS BY L-LACTATE [J].

DROGE, W ;

ROTH, S ;

ALTMANN, A ;

MIHM, S .

CELLULAR IMMUNOLOGY, 1987, 108 (02) :405-416

← 1 2 3 4 →