Dynamic evolution of blood immune-inflammatory descriptors in advanced non-small cell lung cancer undergoing first-line immunotherapy-based regimens

Background The groundbreaking results of Immune Checkpoint Inhibitors (ICIs) in NSCLC still involve a limited subset of cases, thus imposing an optimization of patient selection. With the aim to non-invasively intercept tumor-host events implicated in cancer immune surveillance and response to immunotherapy, we explored the dynamic of blood immune-inflammatory markers in a cohort of advanced NSCLC treated with first-line ICIs. Methods Peripheral blood was prospectively collected at baseline (T0) and at first radiological disease assessment (T1) from 47 consecutive NSCLC patients undergoing first-line ICI-based therapy. We performed a flow-cytometric analysis of circulating CD3+, CD8+, CD4+, NK, NKT and Tregs as their expression of functional molecules (PD-1, Granzyme B [GnzB], Perforin [Perf]) and proliferative index (Ki67). Soluble PD-L1 (sPD-L1) was determined by immunoassay together with Lung Immune Prognostic Index (LIPI: LDH + derived Neutrophil-to-Lymphocyte Ratio). All these parameters were correlated to objective response rate (ORR) according to RECIST v1.1 criteria. Results From October 2020 to August 2021, 47 advanced NSCLC patients candidate to receive first-line ICI-based therapy were enrolled. Median age was 67.8 years (range 41-82), 66% were males and 81% underwent chemo-immunotherapy. ORR resulted 51%. Among baseline parameters, number of metastatic sites, bone lesions and poor LIPI negatively correlated with ORR (p<0.05), while a trend towards favorable response was apparent in tissue PD-L1high cases (ORR=67% vs 28% in PD-L1neg). A significant proliferative burst of CD8+PD-1+ lymphocytes carrying cytotoxic molecules (GnzB+, Perf+) coupled with sPD-L1 decline characterized responders. Conversely, CD8+ GnzB+/Perf+ and NK cells dramatically dropped in non-responders (χ2 test, p<0.01). Furthermore, the kinetic and extent of Treg counteraction, likely triggered by the expanding (Ki67+) pool of effector lymphocytes, appeared to be a distinctive feature of responsive patients. Conclusions Our results suggest that tracking the evolution of blood immune-inflammatory profiles may provide valuable predictors of ICI efficacy in NSCLC patients.