Eosinophil-neutrophil ratio as a sex-dependent prognostic marker in immune checkpoint therapy for metastatic NSCLC and transcriptomic evaluation of intratumoral eosinophil-T cell interaction.
Authors: Kwon Hyunwoo , Li Mingjia , Ma Anjun , Wang Cankun , Chian Kenneth , Gauntner Timothy , Jones Nicholas , Khorasanchi Adam , Spakowicz Daniel , He Kai , Alahmadi Asrar , Memmott Regan Michelle , Kaufman Jacob , Shields Peter G. , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J. , Ma Qin , Li Zihai , Owen Dwight Hall 
Published: June 2024

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Background: The functional role and therapeutic relevance of eosinophils in patients with metastatic NSCLC receiving immune checkpoint inhibitors (ICI) are unclear. Overall survival (OS) is improved among female patients with a high baseline absolute eosinophil count treated with ICI monotherapy. We investigated the prognostic utility of Eosinophil-Neutrophil Ratio (ENR), biologic sex, and OS among patients receiving first-line ICI for metastatic NSCLC. In addition, we analyzed the transcriptomic data from The Cancer Genome Atlas (TCGA) to evaluate the intratumoral eosinophil - T cell crosstalk. Methods: This was a retrospective cohort study of 310 patients with Stage IV NSCLC treated with first-line ICI-based therapies (alone or in combination with chemotherapy). Demographic data are summarized (Table). Baseline peripheral eosinophil and neutrophil counts were collected within 1 week before the start of therapy. Higher ENR was defined as > 75th percentile. OS was plotted using the Kaplan-Meier method and p-values from log-rank test were reported. For TCGA analysis of primary lung adenocarcinoma (LUAD) (n = 248 male; 291 female) and squamous cell carcinoma (LUSC) (n = 371 male; 131 female), normalized mean expression levels of genes belonging to validated signatures of eosinophil, T cell and interferon-gamma (IFNG) pathways were used to calculate Pearson’s correlation. OS was additionally determined after separating the data by regression lines (“above” and “below”). Results: Patients with lower ENR had a median OS of 18.6 months vs 41.3 months in those with higher ENR (p = 0.008, HR: 1.504, 95% Cl: 1.111-2.037). Patients with higher ENR showed a sex difference, with median OS of 24.2 months in males vs 47.0 months in females (p = 0.03, HR: 1.942, 95% Cl: 1.050-3.592). No sex differences in ENR were observed. TCGA analysis of LUAD showed positive correlation between RNA signatures of eosinophils and those of T cells (p < 2.2e-16, r = 0.51) or IFNG signaling (p < 2.2e-16, r = 0.45) without significant sex differences. Similar results were observed with LUSC. Higher expression of eosinophil and T cell or IFNG signatures was not associated with OS in either sex. Conclusions: We demonstrate that peripheral eosinophil count remains a prognostic marker for ICI responsiveness even after accounting for systemic inflammatory response via ENR. Transcriptomic analyses show evidence of interaction between tumor-infiltrating eosinophils and T cells. Future studies need to evaluate the mechanisms by which eosinophil - T cell crosstalk can augment ICI-induced tumor immunity in a sex-dependent manner.[Table: see text]