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.

Abstract

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. The percentage of CD28^-, CD57⁺, KLRG1⁺ among CD8⁺ 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 cut-off 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⁺ CD8⁺ T cells were assessed <i>in vitro</i>. In the ICI discovery cohort (<i>N</i> = 37), SIP cut-off was 39.5%, 27% of patients were SIP⁺. In the ICI validation cohort (<i>N</i> = 46), SIP⁺ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, <i>P</i> = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, <i>P</i> = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, <i>P</i> = 0.02]. SIP⁺ status was significantly associated with circulating specific immunephenotypes, <i>in vitro</i> lower CD8⁺ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (<i>N</i> = 83), SIP⁺ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (<i>N</i> = 61), 11% of patients were SIP⁺. SIP status did not correlate with outcomes upon PCT. 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.<i>See related commentary by Salas-Benito et al., p. 374</i>.