Programmed Cell Death Ligand 1 Expression Is an Independent Prognostic Factor in Colorectal Cancer

Background/Aim: Programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1(PD-L1) axis is associated with immune tolerance via inhibition of T cell activation. The aim of this study was to clarify the significance of PD-1 and PD-L1 expressions and analyze the relationships between PD-1, PD-L1, transforming growth factor-β (TGF-β) and Forkhead box P3 (Foxp3) expressions in colorectal cancer (CRC). Patients and Methods: A total of 116 patients who underwent curative colectomy for stage II/III CRC were included in the study. PD-1, PD-L1, TGF-β, and Foxp3 expressions were examined by immunohistochemistry and related to prognostic factors by Kaplan–Meier. Results: PD-1 expression was correlated with PD-L1, TGF-β, and Foxp3 expressions. Overall survival rates were significantly poorer in the PD-1 and PD-L1-positive groups. Multivariate analysis showed that PD-L1-positive is an independent risk factor. Disease-free survival (DFS) was tended in the PD-L1-positive group. The group with double-positive expression had significantly poorer prognosis. Conclusion: PD-1 and PD-L1 expressions were associated with a poor prognosis and correlated with TGF-β and Foxp3 expressions in patients with CRC.

[1]  K. Hirakawa,et al.  The Prognostic Significance of the Tumor-infiltrating Programmed Cell Death-1+ to CD8+ Lymphocyte Ratio in Patients with Colorectal Cancer. , 2017, Anticancer research.

[2]  Xinwei Zhang,et al.  PD-1 and its ligands are important immune checkpoints in cancer , 2016, Oncotarget.

[3]  W. Chua,et al.  The Potential Value of Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 Inhibitor Therapy. , 2016, Clinical colorectal cancer.

[4]  B. Marian,et al.  Programmed death-ligand 1 expression in rectal cancer , 2016, European Surgery.

[5]  A. Chinnaiyan,et al.  Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: potential opportunities for immunotherapeutic approaches. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  Christina Wu,et al.  Biomarkers for immune therapy in colorectal cancer: mismatch-repair deficiency and others. , 2016, Journal of gastrointestinal oncology.

[7]  P. Googe,et al.  PD‐L1 expression in cutaneous squamous cell carcinoma correlates with risk of metastasis , 2016, Journal of cutaneous pathology.

[8]  Lik Hang Lee,et al.  Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma , 2016, Modern Pathology.

[9]  G. Freeman,et al.  Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. , 2016, Immunity.

[10]  Y. Sano,et al.  Colorectal cancer screening of the general population in East Asia , 2016, Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society.

[11]  M. Shimada,et al.  Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection , 2016, Gastric Cancer.

[12]  James R. Eshleman,et al.  Microsatellite Instability as a Biomarker for PD-1 Blockade , 2016, Clinical Cancer Research.

[13]  H. Liang,et al.  Elevated Levels of SET and MYND Domain-Containing Protein 3 Are Correlated with Overexpression of Transforming Growth Factor-β1 in Gastric Cancer. , 2015, Journal of the American College of Surgeons.

[14]  W. Liang,et al.  Prognostic Significance of Programmed Cell Death 1 (PD-1) or PD-1 Ligand 1 (PD-L1) Expression in Epithelial-Originated Cancer , 2015, Medicine.

[15]  Loise M. Francisco,et al.  RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance , 2014, The Journal of experimental medicine.

[16]  Xiumin Wang,et al.  PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients , 2014, Cancer Immunology, Immunotherapy.

[17]  Li-juan Wang,et al.  B7-H1 Expression Is Associated with Poor Prognosis in Colorectal Carcinoma and Regulates the Proliferation and Invasion of HCT116 Colorectal Cancer Cells , 2013, PloS one.

[18]  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.

[19]  W. Gillanders,et al.  The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer , 2013, Breast Cancer Research and Treatment.

[20]  L. Terracciano,et al.  Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. , 2013, European journal of cancer.

[21]  G. Sauter,et al.  High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer. , 2013, European journal of cancer.

[22]  A. Vandenbark,et al.  Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17β‐oestradiol‐receptor‐positive B cells that up‐regulate PD‐1 on CD4+ Foxp3+ regulatory T cells , 2012, Immunology.

[23]  Stephen M. Douglass,et al.  The role of FOXP3 in the development and metastatic spread of breast cancer , 2012, Cancer and Metastasis Reviews.

[24]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

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

[26]  U. Güth,et al.  Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers , 2012, BMC Cancer.

[27]  Axel Hoos,et al.  Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. , 2011, The New England journal of medicine.

[28]  Matej Horvat,et al.  Microsatellite instability in colorectal cancer , 2011, Radiology and oncology.

[29]  Gerard C Blobe,et al.  Role of transforming growth factor-beta superfamily signaling pathways in human disease. , 2008, Biochimica et biophysica acta.

[30]  G. Freeman,et al.  PD-1 and its ligands in tolerance and immunity. , 2008, Annual review of immunology.

[31]  Lieping Chen,et al.  The new B7s: playing a pivotal role in tumor immunity. , 2007, Journal of immunotherapy.

[32]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[33]  T. Honjo,et al.  Induced expression of PD‐1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. , 1992, The EMBO journal.

[34]  M. Mandalà,et al.  Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. , 2014, Critical reviews in oncology/hematology.

[35]  Sang-Hoon Ahn,et al.  Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer , 2014, Gastric Cancer.

[36]  J. Massagué,et al.  TGFbeta signaling in growth control, cancer, and heritable disorders. , 2000, Cell.

[37]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.