Alexandra Giatromanolaki1, Alison H Banham2, Adrian L Harris3, Michael I Koukourakis4. 1. a Department of Pathology , University Hospital of Alexandroupolis, Democritus University of Thrace , Alexandroupolis , Greece. 2. b Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine , John Radcliffe Hospital , Oxford , UK. 3. c Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine , University of Oxford , Oxford , UK. 4. d Department of Radiotherapy/Oncology , University Hospital of Alexandroupolis, Democritus University of Thrace , Alexandroupolis , Greece.
Abstract
Purpose/Aim: Regulatory FOXP3+ T-cells control the cytotoxic activity of effector cells and may have an essential role in the development of immune tolerance in cancer patients. Programed death ligand 1 PD-L1, expressed on cancer cell membranes also blocks the cytotoxic activity of PD1+ cytotoxic lymphocytes. Materials and Methods: We assessed the immunohistochemical detection of these immune-tolerance related markers in a series of 98 non-small cell lung carcinomas (NSCLC) treated with surgery. The Tumor Infiltration Lymphocyte TIL density (mean number per x400 optical field) and the percentage of FOXP3+ TILs were assessed. Results: PD-L1 expression was directly linked with the TIL density (p = 0.01) and with the extent of infiltration with FOXP3+ TILs, named as the FIL-score (p = 0.01). FIL-score was significantly higher in stage I disease (p = 0.04). IL6 expression was linked with high TIL-score. A low TIL-score, characterizing immune deficient tumors defined a significantly poorer prognosis subgroup of patients (p = 0.03). Stratification of these tumors according to the FIL-score showed that FOXP3 expression by TILs correlated with an even a poorer prognosis in univariate (p = 0.007; median survival 14 vs. 44 months, respectively) and in multivariate analysis (p = 0.01, hazard ratio 4.3). Conclusion: Tumor stroma infiltration by FOXP3+ Tregs is an early event in the progression of NSCLC. Low lymphocytic infiltration defines poor prognosis, which becomes worse when the small numbers of infiltrating lymphocytes characterizing these tumors contain FOXP3 + Tregs. Furthermore, the direct association of FOXP3+ Treg infiltration density with PD-L1 expression by cancer cells implies a co-ordinated immune-suppressive activity in NSCLC.
Purpose/Aim: Regulatory FOXP3+ T-cells control the cytotoxic activity of effector cells and may have an essential role in the development of immune tolerance in cancer patients. Programed death ligand 1 PD-L1, expressed on cancer cell membranes also blocks the cytotoxic activity of PD1+ cytotoxic lymphocytes. Materials and Methods: We assessed the immunohistochemical detection of these immune-tolerance related markers in a series of 98 non-small cell lung carcinomas (NSCLC) treated with surgery. The Tumor Infiltration Lymphocyte TIL density (mean number per x400 optical field) and the percentage of FOXP3+ TILs were assessed. Results: PD-L1 expression was directly linked with the TIL density (p = 0.01) and with the extent of infiltration with FOXP3+ TILs, named as the FIL-score (p = 0.01). FIL-score was significantly higher in stage I disease (p = 0.04). IL6 expression was linked with high TIL-score. A low TIL-score, characterizing immune deficient tumors defined a significantly poorer prognosis subgroup of patients (p = 0.03). Stratification of these tumors according to the FIL-score showed that FOXP3 expression by TILs correlated with an even a poorer prognosis in univariate (p = 0.007; median survival 14 vs. 44 months, respectively) and in multivariate analysis (p = 0.01, hazard ratio 4.3). Conclusion: Tumor stroma infiltration by FOXP3+ Tregs is an early event in the progression of NSCLC. Low lymphocytic infiltration defines poor prognosis, which becomes worse when the small numbers of infiltrating lymphocytes characterizing these tumors contain FOXP3 + Tregs. Furthermore, the direct association of FOXP3+ Treg infiltration density with PD-L1 expression by cancer cells implies a co-ordinated immune-suppressive activity in NSCLC.
Authors: April E Deveaux; Tyler A Allen; Muthana Al Abo; Xiaodi Qin; Dadong Zhang; Brendon M Patierno; Lin Gu; Jhanelle E Gray; Chad V Pecot; Holly K Dressman; Shannon J McCall; Rick A Kittles; Terry Hyslop; Kouros Owzar; Jeffrey Crawford; Steven R Patierno; Jeffrey M Clarke; Jennifer A Freedman Journal: Lung Cancer Date: 2021-01-14 Impact factor: 5.705
Authors: Arik Bernard Schulze; Georg Evers; Dennis Görlich; Michael Mohr; Alessandro Marra; Ludger Hillejan; Jan Rehkämper; Lars Henning Schmidt; Birthe Heitkötter Journal: J Thorac Dis Date: 2020-05 Impact factor: 3.005
Authors: Menno Tamminga; Thijo Jeroen N Hiltermann; Ed Schuuring; Wim Timens; Rudolf Sn Fehrmann; Harry Jm Groen Journal: Clin Transl Immunology Date: 2020-06-12