(T1030-02-12) Elucidating the Role of IL-8 in NSCLC: Integrated Analysis Through Imaging Mass Cytometry, Mass Cytometry, and Single-Cell Sequencing

Purpose: Interleukin-8 (IL-8) plays a pivotal role in non-small cell lung cancer (NSCLC) progression, influencing both tumor growth and immune response dynamics. Recent insights into the heterogeneity and functional status of tumor-infiltrating T cells have underscored their critical impact on antitumor immunity and responses to immunotherapy, paralleling the observed complexity in IL-8 interactions within the tumor microenvironment. This study integrates imaging mass cytometry (IMC), mass cytometry (CyTOF) and single cell sequencing to analyze IL-8 and its implications on the immune landscape, aiming to translate these findings into clinical applications.

Methods: Employing Imaging Mass cytometry (IMC), we localized and quantified IL-8 protein and mRNA expressions in NSCLC tissues, enhancing our spatial understanding of its distribution and activity. Mass cytometry provided systemic quantification of IL-8 across NSCLC samples, allowing for the assessment of its correlation with tumor aggressiveness and immune cell infiltration. Additionally, we utilized single-cell RNA sequencing (scRNA-seq) to map the landscape of tumor-infiltrating T cells, identifying distinct subsets of IL-8-producing CD4+ T cells with innate-like features associated with poor prognosis.

Results: Our comprehensive analysis revealed that high IL-8 expression correlates with an immunosuppressive tumor microenvironment and reduced efficacy of immune checkpoint blockade (ICB) therapies. Furthermore, we discovered a unique subset of IL-8-producing CD4+ T cells that contribute to the immunosuppressive milieu, challenging the effectiveness of standard treatments. These findings highlight the potential of targeting the IL-8-CXCR1/CXCR2 axis as a novel strategy in NSCLC immunotherapy.

Conclusion: By mapping IL-8 expression and its impact on tumor-infiltrating lymphocytes in NSCLC, this study provides crucial insights that bridge molecular oncology with clinical strategies. The identification of IL-8 as a mediator of immune suppression and its role in reducing the effectiveness of Immune checkpoint blockade therapy emphasizes the need for innovative therapeutic approaches targeting this axis. Our findings advocate for the inclusion of IL-8 in the biomarker panel for NSCLC, potentially improving patient stratification and personalizing therapeutic interventions to counteract its detrimental effects on tumor immunity. Future research will focus on validating these observations in clinical trials.