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.

The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC / Mazzaschi, Giulia; Facchinetti, Francesco; Missale, Gabriele; Canetti, Diana; Madeddu, Denise; Zecca, Alessandra; Veneziani, Michele; Gelsomino, Francesco; Goldoni, Matteo; Buti, Sebastiano; Bordi, Paola; Aversa, Franco; Ardizzoni, Andrea; Quaini, Federico; Tiseo, Marcello. - In: LUNG CANCER. - ISSN 0169-5002. - 127:(2019), pp. 153-163. [10.1016/j.lungcan.2018.11.038]

The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC

Mazzaschi, Giulia;Facchinetti, Francesco;Missale, Gabriele;Madeddu, Denise;Goldoni, Matteo;Buti, Sebastiano;Bordi, Paola;Aversa, Franco;Quaini, Federico;Tiseo, Marcello
2019

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.
The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC / Mazzaschi, Giulia; Facchinetti, Francesco; Missale, Gabriele; Canetti, Diana; Madeddu, Denise; Zecca, Alessandra; Veneziani, Michele; Gelsomino, Francesco; Goldoni, Matteo; Buti, Sebastiano; Bordi, Paola; Aversa, Franco; Ardizzoni, Andrea; Quaini, Federico; Tiseo, Marcello. - In: LUNG CANCER. - ISSN 0169-5002. - 127:(2019), pp. 153-163. [10.1016/j.lungcan.2018.11.038]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2853622
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