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

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+, 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 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 objective response rate (ORR; 0% vs. 30%, P = 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 = 0.009] and median overall survival, OS [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 IL2 and higher TNFα and IFNγ 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 patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT. See related commentary by Salas-Benito et al., p. 374

Senescent T cells: a potential biomarker and target for cancer therapy

“…Therefore, the frequency of senescent T cells may act as a potential biomarker to predict the response to ICIs. In advanced NSCLC and melanoma patients treated with PD-1/PD-L1 inhibitors, a high level of circulating senescent CD8 + T cells, with limited proliferative capacity and lower IL-2 and higher TNF-α and IFN-γ production [68] , was significantly correlated with resistance to ICIs [69] and a poor overall response rate (ORR), median PFS and OS [68 , 70] .…”

A “two-hit” (chemo)therapy to improve checkpoint inhibition in cancer

“…As V and C140 dosages found to significantly improve CI preclinical activity are suitable for a combinatorial use in cancer patients, clinical trials in TNBC and B-cell lymphoma are now planned to confirm the efficacy of this “two-hit” plus CI therapy. It will be of interest to investigate in enrolled patients a number of emerging candidate biomarkers of immune cell activation, including: a) APC activation patterns; b) the generation of new TCF1 + stem-like CD8+ T-cells; c) CXCL13 and CCR5 overexpressing, neo-antigen reactive CD8+ T cells [ 8 ]; d) newly generated IFN-γ–expressing resident memory T cells [ 9 ]; e) pre-treatment values of senescent CD28-CD57+KLGR1+CD8+ T cells [ 10 ]; and f) post-treatment values of proliferating PD-1+CD8+ T cells [ 11 ]. The goal of such a therapy, in fact, is the generation of a long-lasting anti-tumor immunity in treated cancer patients.…”

Efficacy of Anti-PD-1/PD-L1 Monotherapy or Combinational Therapy in Patients Aged 75 Years or Older: A Study-Level Meta-Analysis

“…In contrary to the previous meta-analysis, we observed the better survival outcomes only in patients < 75 years, but not in patients ≥ 75 years. It had been reported that aging is associated with immune dysregulation, such as the decreased TCR diversity in CD4+ T cells (14) and CD8+ T cells (15), but not the T-cell immunosenescence (29). In addition, aging-associated adipocyte accumulation in the bone marrow also contributes to reduced hematopoiesis with age (30), and hematopoiesis becomes skewed toward myeloid and away from lymphoid lineages with age (16).…”