2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.13: Temporal Immune Evolution in a Murine EML4-ALK NSCLC Model: Genomic, Proteomic, and Drug Co-Culture Characterization

PP01.13: Temporal Immune Evolution in a Murine EML4-ALK NSCLC Model: Genomic, Proteomic, and Drug Co-Culture Characterization

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The study investigates the immune evolution in a murine model of EML4-ALK non-small cell lung cancer (NSCLC), focusing on the interaction between genomic, proteomic, and therapeutic interventions. It primarily evaluates the efficacy of tyrosine kinase inhibitors (TKIs) like Alectinib and Lorlatinib, and an immune checkpoint inhibitor (Anti-PD-1) on tumor growth and immune response over time.<br /><br />Key findings include that TKI treatments significantly inhibit tumor growth and enhance survival, while Anti-PD-1 does not show a significant difference from the control. Immune checkpoint genes in the tumor exhibit decreased expression with Alectinib and Lorlatinib over time. The study demonstrates that these treatments cause considerable upregulation and downregulation of immune-related genes at various time points. The TKI treatments increased CD3 T cells in the tumor core, with decreased CD206 macrophages at later stages compared to control.<br /><br />The study uses an immune-competent mouse model with TP53 wild-type mice, where the EML4 and ALK chromosomal rearrangement is induced via a CRISPR/Cas9 system. The systemic immunity remains minimal across all treatments, and it finds that tumor peripheries have a higher concentration of immune cells than cores. A 3D co-culture drug testing model was established to evaluate cell viability under drug combination treatments.<br /><br />This research highlights the need for a better understanding of immune microenvironments and temporal immune evolution to optimize therapeutic interventions in ALK NSCLC. The goal is to identify immunological drivers for growth and treatment response, as well as optimal treatment windows for immunotherapies. Despite the effectiveness of TKI therapy, further research is needed to understand why Anti-PD-1 therapy shows limited effects in these models.

Asset Subtitle

Marisa Aikins

Keywords

immune evolution

EML4-ALK

non-small cell lung cancer

tyrosine kinase inhibitors

Alectinib

Lorlatinib

Anti-PD-1

tumor microenvironment

CRISPR/Cas9

immune checkpoint