The expression and clinical relevance of PD-1, PD-L1, and TP63 in patients with diffuse large B-cell lymphoma

Abstract Latest study showed that a novel translocation between programmed cell death ligand 1 (PD-L1) (cluster of differentiation 274) and TP63 (tumor protein 63) can be found in diffuse large B-cell lymphoma (DLBCL), resulting in their conjunct overexpression in tumor cells at RNA level. However, the expressed pattern of these 2 genes at protein level in DLBCL remains largely unknown, and the clinical relevance of PD-L1 and TP63 expression in DLBCL are also unclear. Tumor tissues from 76 Chinese DLBCL patients were immunostained for programmed cell death 1 (PD-1), PD-L1, and TP63 using the EnVision system. Clinical relevance of PD-1, PD-L1, and TP63 in 74 DLBCL were analyzed by chi-square test, the Kaplan–Meier curves with log rank test, and Cox's proportional hazards regression model. PD-1 was mainly expressed in tumor-infiltrating lymphocytes (TILs) of 39.5% patients. PD-L1 was expressed in tumor cells of 26.3% patients, and TP63 was immunostained in nucleoli of tumor cells of 31.6% cases. PD-1 expression was significantly associated with the patients’ gender and B symptoms (P = 0.032, P = 0.026). DLBCL with PD-L1 or TP63 expression in tumor cells showed low International Prognostic Index (IPI) score (P = 0.007, P = 0.009). PD-1+ TILs was related to prolonged overall survival rate (OS) of DLBCL patients (P = 0.02), whereas PD-L1 expression was associated with worse clinical outcome of patients (P = 0.049). Immunoreactivity of TP63 was not correlated with patients’ survival time. Besides, PD-1 expression, patients’ age, Ann Arbor stage, and IPI score were significant prognostic markers for OS, but PD-L1 and TP63 had no prognostic significance. PD-1, PD-L1, and TP63 are frequently expressed in DLBCL. PD-1/PD-L1/TP63 blockade may be a potential therapeutic strategy for some patients.

[1]  Guoqiang Chen,et al.  CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling , 2016, Journal of Hematology & Oncology.

[2]  S. Gettinger,et al.  Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Kui Wu,et al.  Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. , 2016, Blood.

[4]  D. Heo,et al.  Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas , 2016, Histopathology.

[5]  Satoru Miyano,et al.  Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers , 2016, Nature.

[6]  Q. Pan-Hammarström,et al.  Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1/PD-L1 axis activating intracellular AKT/mTOR pathway in tumor cells , 2016, Oncotarget.

[7]  K. Akashi,et al.  Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. , 2015, Blood.

[8]  Xuyou Zhu,et al.  Clinical significance of programmed death ligand-1 (PD-L1) in colorectal serrated adenocarcinoma. , 2015, International journal of clinical and experimental pathology.

[9]  G. Freeman,et al.  The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. , 2015, Clinical therapeutics.

[10]  F. Cappuzzo,et al.  Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. , 2015, The Lancet. Oncology.

[11]  M. Millenson,et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. , 2015, The New England journal of medicine.

[12]  Yan Liu,et al.  PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation , 2015, Journal of Translational Medicine.

[13]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[14]  G. Freeman,et al.  PD-L1 expression in nonclear-cell renal cell carcinoma. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[15]  K. Naresh,et al.  Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma , 2014, Virchows Archiv.

[16]  K. Tarte,et al.  High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial , 2014, Leukemia.

[17]  J. Taube,et al.  Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy , 2014, Clinical Cancer Research.

[18]  R. Figlin,et al.  Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions. , 2014, Clinical advances in hematology & oncology : H&O.

[19]  R. Davis,et al.  Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. , 2014, The Lancet. Oncology.

[20]  P. Houghton,et al.  p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage* , 2013, The Journal of Biological Chemistry.

[21]  Travis J Cohoon,et al.  Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. , 2013, Cancer discovery.

[22]  Antoni Ribas,et al.  Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. , 2013, The New England journal of medicine.

[23]  Jun Hu,et al.  PTEN Loss Increases PD-L1 Protein Expression and Affects the Correlation between PD-L1 Expression and Clinical Parameters in Colorectal Cancer , 2013, PloS one.

[24]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[25]  Ryan D. Morin,et al.  TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma. , 2012, Blood.

[26]  R. Gascoyne,et al.  TBL 1 XR 1 / TP 63 : a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma , 2012 .

[27]  E. Goode,et al.  Tumor-Infiltrating Programmed Death Receptor-1+ Dendritic Cells Mediate Immune Suppression in Ovarian Cancer , 2011, The Journal of Immunology.

[28]  G. Pinkus,et al.  Programmed Death Ligand 1 Is Expressed by Non–Hodgkin Lymphomas and Inhibits the Activity of Tumor-Associated T Cells , 2011, Clinical Cancer Research.

[29]  A. Tzankov,et al.  Diagnostic and Prognostic Utility of PD-1 In B Cell Lymphomas , 2010, Disease markers.

[30]  J. Pereira,et al.  p63 Protein expression in high risk diffuse large B-cell lymphoma , 2008, Journal of Clinical Pathology.

[31]  R. Yamamoto,et al.  PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. , 2007, Blood.

[32]  N. Tsuneyoshi,et al.  Clinico‐pathological characteristics of p63 expression in B‐cell lymphoma , 2006, Cancer science.

[33]  G. Freeman,et al.  Programmed Death-1 (PD-1) is a Marker of Germinal Center-associated T Cells and Angioimmunoblastic T-Cell Lymphoma , 2006, The American journal of surgical pathology.

[34]  L. Staudt,et al.  Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma , 2003, The Journal of experimental medicine.

[35]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[36]  M Mazumdar,et al.  Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  Christopher P. Crum,et al.  p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development , 1999, Nature.

[38]  H. Vogel,et al.  p63 is a p53 homologue required for limb and epidermal morphogenesis , 1999, Nature.

[39]  T. Honjo,et al.  Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. , 1996, International immunology.

[40]  A. Bradley,et al.  p 63 is a p 53 homologue required for limband epidermalmorphogenesis , 2022 .