WCLC 2025 - Posters & ePosters-P2.02.32 Homeostatic Dysregulation of Systemic CD8+ T Cell Compartment in Lung Cancer Patients

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This study investigates the systemic homeostatic dysregulation of CD8 T cells in lung cancer patients and its impact on immune responses and therapy outcomes. Analyzing peripheral blood samples from 349 lung cancer patients and 53 healthy donors using flow cytometry, single-cell RNA sequencing, and T cell receptor (TCR) sequencing, the researchers focused on CD8 T cell subsets, their differentiation states, proliferation capacity, and gene expression linked to immune homeostasis. The study also assessed clinical responses to immune checkpoint inhibitor (ICI) therapy across four patient cohorts.<br /><br />Results showed that lung cancer patients exhibit altered peripheral blood CD8 effector memory (Tem) subsets, particularly an increase in CD8 double-negative Tem (DN-Tem) cells. These increased DN-Tem cells arise through both clonal expansion-dependent and independent mechanisms and display altered transcriptional profiles indicative of loss of quiescence, suggesting dysregulated differentiation. The expanded DN-Tem cells are clonally diverse and associated with the generation of GZMK-expressing DN-Tem cells.<br /><br />Importantly, this systemic dysregulation of CD8 T cells correlates with poor clinical response to ICI therapy, signifying a novel immune evasion mechanism orchestrated by lung tumors. The accumulation of dysfunctional effector memory subsets reflects a disruption of systemic immune homeostasis beyond the tumor microenvironment.<br /><br />The study's findings, summarized under the concept “Cancer-associated Homeostatic dysregulation Accelerating uncOntrolled differentiation of Systemic CD8 T cells” (CHAOS), highlight that lung cancer induces broad impairment of the systemic CD8 T cell compartment. This insight into tumor-induced systemic immune alterations provides a foundation for developing enhanced immunotherapeutic strategies targeting these dysregulated T cell populations to improve lung cancer patient outcomes.

Asset Subtitle

Ju Sik Yun

Meta Tag

Speaker Ju Sik Yun

Topic Tumor Biology – Preclinical Biology

Keywords

CD8 T cells

lung cancer

immune homeostasis

effector memory T cells

double-negative Tem cells

clonal expansion

transcriptional dysregulation

immune checkpoint inhibitor therapy

systemic immune dysregulation

immunotherapy outcomes