Peripheral immune cell subsets as potential predictors of benefit from immune checkpoint blockade therapy in small cell lung cancer.

Abstract

Small cell lung cancer (SCLC) is a lethal neoplasia. Chemotherapy (Ct) plus immune checkpoint blockade therapy (ICBt) is now the standard of care although limited survival benefit. Lack of biomarkers of response leads to suboptimal patient selection, distorting results of clinical trials. Deciphering the ICBt-driven peripheral immune events may recognize those patients who benefit the most. Here, we characterize early peripheral immune kinetics in SCLC patients treated with Ct + ICBt with improved survival. SCLC patients from 8 centers were prospectively recruited into 3 cohorts. Cohort 1 (N = 24) include patients treated with Ct. Cohort 2 (N = 37) comprise patients treated with Ct + anti-CTLA-4, and cohort 3 (N = 20) patients treated with Ct + anti-PD-1/PD-L1. Peripheral blood mononuclear cells (PBMCs) were obtained prior to treatment initiation and 3-4 weeks after (before cycle 2). Variation in proliferation, senescence, adhesion, immunosuppression, and checkpoints markers was assessed by Fluorescence-Activated Cell Sorting (FACS). Kaplan-Meier and log-rank test were used for survival analysis. MaxStat was used to calculate cut points. A p-value <0.05 was considered statistically significant. We found 6 independent cellular subsets whose modulation shortly after the start of ICBt identify patients with improved survival. An increase in CD8+CD103+Ki67+ cells identify survival benefit in cohorts 1 and 3 (p=0.043; 0.0033). In ICBt cohorts 2 and 3, an upregulation of Ki67 in total CD4+ (p=0.012; 0.0027) and CD4+PD-1+ T cells (p=0.026; 0.027), predicted longer survival, while a downregulation of CD4+ICOS+ T cells (p=0.025; 0.011) identified survival benefit in these same ICBt cohorts. Expansion of Ki67+ and ICOS+ (p=0.0024; 0.0074) CD8+ T cells was also observed in CD8+ T cells from long survivors exclusively from cohort 2. This study provides one of the few longitudinal assessments of peripheral immune dynamics in SCLC patients receiving ICBt, suggesting that early on-treatment changes, evaluated relative to each patient's own baseline levels, may provide greater predictive value than single-timepoint inter-patient comparisons.