Giulia Mazzaschi1, Francesco Facchinetti2, Gabriele Missale3, Diana Canetti4, Denise Madeddu5, Alessandra Zecca6, Michele Veneziani7, Francesco Gelsomino8, Matteo Goldoni9, Sebastiano Buti10, Paola Bordi11, Franco Aversa12, Andrea Ardizzoni13, Federico Quaini14, Marcello Tiseo15. 1. Department of Medicine and Surgery, University of Parma, Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: giulia.mazzaschi@studenti.unipr.it. 2. Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: francescofacchinetti2@gmail.com. 3. Infectious Diseases and Hepatology Unit, Laboratory of Viral Immunopathology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: gmissale@ao.pr.it. 4. Infectious Diseases and Hepatology Unit, Laboratory of Viral Immunopathology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: di.canetti@gmail.com. 5. Department of Medicine and Surgery, Hematology and Bone Marrow Transplantation, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: denise.madeddu@unipr.it. 6. Infectious Diseases and Hepatology Unit, Laboratory of Viral Immunopathology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: alessandra.zecca@studenti.unipr.it. 7. Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: michele.veneziani@studenti.unipr.it. 8. Medical Oncology Unit, Sant'Orsola-Malpighi University Hospital, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: fgelsomino@ao.pr.it. 9. Department of Medicine and Surgery, Medical Statistics, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy. Electronic address: matteo.goldoni@unipr.it. 10. Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: sbuti@ao.pr.it. 11. Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: paolabordi@yahoo.it. 12. Department of Medicine and Surgery, Hematology and Bone Marrow Transplantation, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: franco.aversa@unipr.it. 13. Medical Oncology Unit, Sant'Orsola-Malpighi University Hospital, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: andrea.ardizzoni2@unibo.it. 14. Department of Medicine and Surgery, Hematology and Bone Marrow Transplantation, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: federico.quaini@unipr.it. 15. Department of Medicine and Surgery, University of Parma, Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address: mtiseo@ao.pr.it.
Abstract
INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters. METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes. RESULTS: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg. CONCLUSION: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLCpatients receiving nivolumab was performed to identify potentially predictive parameters. METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLCpatients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes. RESULTS:KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg. CONCLUSION: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
Authors: Emily J Pomeroy; John T Hunzeker; Mitchell G Kluesner; Walker S Lahr; Branden A Smeester; Margaret R Crosby; Cara-Lin Lonetree; Kenta Yamamoto; Laura Bendzick; Jeffrey S Miller; Melissa A Geller; Bruce Walcheck; Martin Felices; Beau R Webber; Timothy K Starr; Branden S Moriarity Journal: Mol Ther Date: 2019-10-15 Impact factor: 11.454
Authors: Nicola Principe; Joel Kidman; Richard A Lake; Willem Joost Lesterhuis; Anna K Nowak; Alison M McDonnell; Jonathan Chee Journal: Front Oncol Date: 2021-04-27 Impact factor: 6.244
Authors: Lisanne Heim; Zuqin Yang; Patrick Tausche; Katja Hohenberger; Mircea T Chiriac; Julia Koelle; Carol-Immanuel Geppert; Katerina Kachler; Sarah Miksch; Anna Graser; Juliane Friedrich; Rakshin Kharwadkar; Ralf J Rieker; Denis I Trufa; Horia Sirbu; Markus F Neurath; Mark H Kaplan; Susetta Finotto Journal: Front Immunol Date: 2022-04-20 Impact factor: 8.786