API5 confers tumoral immune escape through FGF2-dependent cell survival pathway.
Identifying immune escape mechanisms used by tumors may define strategies to sensitize them to immunotherapies to which they are otherwise resistant. In this study, we show that the antiapoptotic gene API5 acts as an immune escape gene in tumors by rendering them resistant to apoptosis triggered by tumor antigen-specific T cells. Its RNAi-mediated silencing in tumor cells expressing high levels of API5 restored antigen-specific immune sensitivity. Conversely, introducing API5 into API5(low) cells conferred immune resistance. Mechanistic investigations revealed that API5 mediated resistance by upregulating FGF2 signaling through a FGFR1/PKCδ/ERK effector pathway that triggered degradation of the proapoptotic molecule BIM. Blockade of FGF2, PKCδ, or ERK phenocopied the effect of API5 silencing in tumor cells expressing high levels of API5 to either murine or human antigen-specific T cells. Our results identify a novel mechanism of immune escape that can be inhibited to potentiate the efficacy of targeted active immunotherapies.
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University;
Kyung Hee
KH
Noh
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University; Immunotherapy Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea;
Seok-Ho
SH
Kim
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University;
Jin Hee
JH
Kim
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University;
Kwon-Ho
KH
Song
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University;
Young-Ho
YH
Lee
Department of Immunology, College of Medicine, Konkuk University, Chungju, South Korea;
Tae Heung
TH
Kang
Department of Immunology, College of Medicine, Konkuk University, Chungju, South Korea; Center for RNA Interference and Non-coding RNA;
Hee Dong
HD
Han
Department of Gynecologic Oncology and Center for RNA Interference and Non-coding RNA;
Anil K
AK
Sood
Global Research Lab, Division of Brain Korea 21 Program for Biomedical Science and Department of Biochemistry, Korea University College of Medicine, Seoul;
Joanne
J
Ng
Global Research Lab, Division of Brain Korea 21 Program for Biomedical Science and Department of Biochemistry, Korea University College of Medicine, Seoul; Department of Melanoma Medical Oncology and Immunology, U.T. MD Anderson Cancer Center, Houston Texas; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Kwanghee
K
Kim
Global Research Lab, Division of Brain Korea 21 Program for Biomedical Science and Department of Biochemistry, Korea University College of Medicine, Seoul;
Chung Hee
CH
Sonn
Department of Pathology, University of Chicago, Chicago, Illinois; and.
Vinay
V
Kumar
Department of Melanoma Medical Oncology and Immunology, U.T. MD Anderson Cancer Center, Houston Texas; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington twkim0421@korea.ac.kr kyunglee@korea.ac.kr cyee@mdanderson.org.
Cassian
C
Yee
Global Research Lab, Division of Brain Korea 21 Program for Biomedical Science and Department of Biochemistry, Korea University College of Medicine, Seoul; twkim0421@korea.ac.kr kyunglee@korea.ac.kr cyee@mdanderson.org.
Kyung-Mi
KM
Lee
Authors' Affiliations: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University; Global Research Lab, Division of Brain Korea 21 Program for Biomedical Science and Department of Biochemistry, Korea University College of Medicine, Seoul; twkim0421@korea.ac.kr kyunglee@korea.ac.kr cyee@mdanderson.org.
Tae Woo
TW
Kim
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000276:immunology*; D005419:Flavonoids / Q000494:pharmacology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*
C108386:API5 protein, human; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002867:Chromones; D005419:Flavonoids; D007093:Imidazoles; D008565:Membrane Proteins; D009025:Morpholines; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D016222:Fibroblast Growth Factor 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one