Circulating T-cell immunosenescence in advanced non-small cell lung cancer patients treated with single agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy.

Purpose CD28, CD57 and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in advanced NSCLC (aNSCLC) patients is unknown. Experimental design The percentage of CD28-, CD57+, KLRG1+ among CD8+ T-cells (SIP) was assessed by flow cytometry on blood from aNSCLC patients before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and aNSCLC patients treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T-cells were assessed in vitro. Results In the ICI discovery cohort (N=37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N=46), SIP+ status was found in 28% of patients and significantly correlated with worse ORR (0% vs 30%, p=0.04), median (m) PFS [1.8 (95% CI 1.3-NR) vs 6.4 (95% CI 2-19) months, p=0.009] and mOS [2.8 (95% CI 2.0-NR) vs 20.8 (95% CI 6.0-NR) months, p=0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in-vitro lower CD8+ T-cells proliferation, lower IL-2 and higher TNFa and IFNg production. In the ICI-pooled population (N=83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS and OS. In PCT cohort (N=61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT. Conclusions Circulating T-cell immunosenescence is observed in up to 28% of aNSCLC patients and correlates with lack of benefit from ICI but not from PCT.