FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas.
The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco-Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
P J
PJ
Brown
Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia.
K K
KK
Wong
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
S L
SL
Felce
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
L
L
Lyne
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
H
H
Spearman
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
E J
EJ
Soilleux
Department of Haematology, Roskilde Hospital, Roskilde, Denmark.
L M
LM
Pedersen
Department of Pathology, Odense University Hospital, Odense, Denmark.
M B
MB
Møller
Department of Pathology, Odense University Hospital, Odense, Denmark.
T M
TM
Green
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
D M
DM
Gascoyne
NDCLS, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
A H
AH
Banham
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D059805:HLA-DR alpha-Chains / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D011241:Prednisone / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D000069283:Rituximab; D015398:Signal Transduction; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*; D014750:Vincristine / Q000627:therapeutic use
D058846:Antibodies, Monoclonal, Murine-Derived; D000944:Antigens, Differentiation, B-Lymphocyte; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D059805:HLA-DR alpha-Chains; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C571759:R-CHOP protocol; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; C045084:invariant chain; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone