WCLC 2025 - Posters & ePosters-P1.11.54 Lack of Durable Response to ICI Therapy in Advanced NSCLC: The Role of Circulating Lazy T Cells

Pdf Summary

This study investigates immune factors contributing to the differential response to immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients. Only about 20% of patients show durable responses to ICI therapy, while 14-37% rapidly progress, yet reliable biomarkers to predict outcomes remain elusive. The researchers compared long responders (LR) and fast progressors (FP) treated with ICIs, analyzing peripheral blood immune cells, cytokine production, autoantibody effects, and monocyte antigen presentation capacity.<br /><br />Both groups had similar proportions of circulating CD4 and CD8 T cells, but LR patients’ T cells exhibited greater interferon-gamma (IFN-γ) production upon stimulation, indicative of stronger immune activation. FP patients' T cells could still produce IFN-γ but responded differently under prolonged IL-2 exposure or nivolumab treatment. Regulatory T cells (Tregs), which modulate immune responses through cytokines, were more abundant in LR patients, while FP patients had higher circulating TGF-β1, a suppressive cytokine. B cell quantities and immunoglobulin levels were comparable, but only FP patient autoantibodies inhibited growth of NSCLC tumor cells derived under ICI pressure, suggesting a unique immune modulation.<br /><br />Monocyte analysis revealed that intermediate monocytes in LR patients expressed higher levels of HLA-DR (important for antigen presentation), whereas FP patients showed a greater than 50% reduction in HLA-DR expression on these cells. Elevated plasma levels of PTX3, an inhibitor of antigen presentation and promoter of tumor plasticity, were seen in FP patients, possibly contributing to their poor response.<br /><br />In conclusion, durable ICI responses in advanced NSCLC correlate with enhanced T cell IFN-γ production, higher circulating Tregs with lower TGF-β1, and robust antigen-presenting monocytes with high HLA-DR. Conversely, fast progression associates with impaired antigen presentation, elevated PTX3, and autoantibody-mediated tumor growth inhibition. These findings highlight circulating immune components, especially monocytes and regulatory T cells, as potential biomarkers and targets to improve ICI therapy monitoring and efficacy in NSCLC.

Asset Subtitle

Arianna Palladini

Meta Tag

Speaker Arianna Palladini

Topic Metastatic Non-small Cell Lung Cancer – Immunotherapy

Keywords

immune checkpoint inhibitors

non-small cell lung cancer

immune biomarkers

T cell interferon-gamma production

regulatory T cells

TGF-beta1

autoantibodies

monocyte antigen presentation

HLA-DR expression

PTX3