2022 World Conference on Lung Cancer (Posters)-P2.12-05. Cancer and Atopy: Parallel Drivers? IL-4 Blockade Synergizes with PD-L1 Blockade to Reverse Type-2Mediated Immunosuppression

P2.12-05. Cancer and Atopy: Parallel Drivers? IL-4 Blockade Synergizes with PD-L1 Blockade to Reverse Type-2Mediated Immunosuppression

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This study explores the role of IL-4, a type-2 cytokine, in cancer and its potential synergy with PD-L1 blockade in promoting antitumor immune responses. The authors used high-dimensional immune profiling to analyze human NSCLC lesions and identified functionally distinct populations of macrophages and a tumor-enriched dendritic cell program associated with immunosuppression. They also found similar cells in a mouse model of lung cancer.<br /><br />Using single-cell RNA sequencing and CITE-seq, the authors discovered that immunosuppressive tumor-infiltrating myeloid cells express an IL-4 responsive transcriptional program upon tumor antigen uptake, suggesting a role for type-2 immunity in creating an immunopermissive intratumoral environment. To investigate the effect of IL-4 signaling on tumor growth, IL-4 was blocked in tumor-bearing mice in combination with PD-L1 blockade. This dual blockade resulted in reduced lung tumor burden and increased cytotoxic CD8 T cell infiltration.<br /><br />The synergistic effect of IL-4 and PD-L1 blockade was observed across multiple preclinical cancer models. However, the response varied depending on the tissue site, suggesting context-dependent interactions between the tissue microenvironment and immune cells.<br /><br />Based on these findings, the authors are now exploring the role of IL-4 blockade in lung cancer patients using dupilumab, an anti-IL-4Rα antibody used for treating atopic diseases. They are investigating whether the addition of dupilumab to checkpoint blockade can rescue clinical response to immunotherapy in NSCLC patients whose disease has progressed on PD-(L)1 therapies.<br /><br />Overall, the study reveals a strong type-2 immune program in intra-tumoral myeloid cells, induced upon tumor antigen uptake, which is associated with an immunosuppressive transcriptional profile. The results suggest that IL-4 blockade can augment antitumor immunity and synergize with PD-L1 blockade in a context-dependent manner. Ongoing clinical trials will further investigate the potential of IL-4 blockade in lung cancer patients.

Asset Subtitle

Thomas Marron, United States

Meta Tag

Speaker Thomas Marron, United States

Topic Tumour Biology and Biomarkers - Immune Biology & Immunotherapy

Keywords

IL-4

cancer

PD-L1 blockade

immune responses

macrophages

dendritic cells

immunosuppression

tumor growth

cytotoxic T cells

clinical trials