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: Hyunwoo Kwon, Mingjia Li, Anjun Ma, Cankun Wang, Kenneth Chian, Timothy Gauntner, Nicholas Jones, Adam Khorasanchi, Daniel Spakowicz, Kai He, Asrar Alahmadi, Regan Michelle Memmott, Jacob Kaufman, Peter G. Shields, David Paul Carbone, Gregory Alan Otterson, Carolyn J. Presley, Qin Ma, Zihai Li, Dwight Hall Owen
Journal: Journal of Clinical Oncology (2024)

8586 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 &gt; 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 &lt; 2.2e-16, r = 0.51) or IFNG signaling (p &lt; 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]