Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in nonsmall cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed.Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed.Results: PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8 pos lymphocytes lacking PD-1 inhibitory receptor had a longer overall survival (OS: HR ¼ 2.268; 95% CI, 1.056-4.871, P ¼ 0.03). PD-1-to-CD8 ratio resulted in a prognostic factor both on univariate (HR ¼ 1.952; 95% CI, 1.34-3.12, P ¼ 0.001) and multivariate (HR ¼ 1.943; 95% CI, 1.38-2.86, P ¼ 0.009) analysis. Moreover, low PD-1 incidence among CD8 pos cells was a distinctive feature of nivolumab-treated patients, showing clinical benefit with a prolonged progressionfree survival (PFS: HR ¼ 4.51; 95% CI, 1.45-13.94, P ¼ 0.004).Conclusions: In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1-negative effector T lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC.
e14514 Background: Detection of predictive markers of anti-PD-1/PD-L1 antibodies activity is of pivotal interest in non-small cell lung cancer (NSCLC). This study aimed to identify a circulating immuno-profile as predictor of outcome in NSCLC patients treated with nivolumab Methods: A peripheral blood immuno-profile evaluation was performed at baseline (T0), after 2 (T1) and 4 cycles (T2) of bi-weekly nivolumab in advanced pre-treated NSCLC patients from two Italian Institutions. First tumor assessment was performed after 4 cycles and then every 2 months. FACS analysis of lymphocyte subpopulations [CD3, CD4, CD8, NK (CD56), Treg (FOXP3) and MDSC] was performed. Absolute and % changes of lymphocyte subsets together with their functional and proliferative activity were assessed. Quali-quantitative leucocyte composition at baseline and its variation during therapy were correlated with tumor response and survival. Results: In the overall population of 54 treated patients, baseline Neutrophil-to-Lymphocyte ratio and NK count, lymphocyte count and CD4 variations during therapy showed a statistically significant prognostic role (p < 0.001; p = 0.012; p < 0.001; p = 0.010, respectively). Among 31 patients (squamous carcinoma, n = 17; adenocarcinoma, n = 14) in which all 3 time-points samples were available, 19 were responders (response and stable disease) and 12 non-responders. In responders, absolute numbers of total NK and NKCD56dim subset were higher at baseline and their increase between T0 and T1 was statistically significant (p < 0.05). Responders also displayed increased cytotoxic capability as shown by a higher baseline expression of CD3ζ, perforin and granzyme in NKCD56dim subset. No significant variation was documented in absolute number and functional activity of CD4+ and CD8+ lymphocytes. A higher percentage of CD8+PD-1+ cells at baseline was observed in responders, while non-responders showed a statistically significant increase in the absolute number of MDSC during therapy (p < 0.05). Conclusions: The number and function of NKs and the frequency of PD-1 expression in CD8+ cells could represent predictive peripheral immuno-biomarkers for nivolumab treatment in advanced NSCLC.
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