Circulating T-cell immunosenescence in patients with advanced non⇓small cell lung cancer 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 patients with advanced non–small cell lung cancer (aNSCLC) is unknown. Experimental Design: The percentage of CD28, CD57^þ, KLRG1^þ among CD8^þ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cutoff was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP^þ CD8^þ T cells were assessed in vitro. Results: In the ICI discovery cohort (N ¼ 37), SIP cut-off was 39.5%, 27% of patients were SIP^þ. In the ICI validation cohort (N ¼ 46), SIP^þ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P ¼ 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P ¼ 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P ¼ 0.02]. SIP^þ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8^þ T cells proliferation, lower IL2 and higher TNFa and IFNg production. In the ICI-pooled population (N ¼ 83), SIP^þ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N ¼ 61), 11% of patients were SIP^þ. SIP status did not correlate with outcomes upon PCT. Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.