2024 World Conference on Lung Cancer (WCLC) - Posters-P3.13D.04 Extrachromosomal MYC-Paralogs Amplification Defines Immunosuppressive Microenvironment with Metastatic Potential in Small Cell Lung Cancer

P3.13D.04 Extrachromosomal MYC-Paralogs Amplification Defines Immunosuppressive Microenvironment with Metastatic Potential in Small Cell Lung Cancer

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This study explores the role of extrachromosomal circular DNA (ecDNA) in amplifying MYC-paralogs—specifically MYC, MYCN, and MYCL—in small cell lung cancer (SCLC). This amplification is critical as it may shape an immunosuppressive tumor microenvironment and contribute to the cancer's metastatic potential, which presents challenges in current immunotherapy treatments.<br /><br />Methods for the study included real-time polymerase chain reaction (qPCR) to investigate MYC-paralog copy numbers, RNA-sequencing, and flow cytometry to analyze controlled and drug-treated SCLC cell lines. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect MYC-paralog overexpression and amplification in 42 clinical SCLC samples. Imaging mass cytometry (IMC) further characterized tumor microenvironments with a 40-plex antibody panel.<br /><br />Results showed significant MYC-paralog amplification in SCLC samples, particularly a 20-fold increase in T1 stage treatment-naïve patients. This amplification correlates with a suppressive tumor microenvironment, evidenced by reduced T cell infiltration and increased expressions of Ki-67, VEGFA, FAP, and FOXP3. Activation of immune-related pathways following the elimination of ecMYC suggests potential therapeutic targets. Furthermore, expression profiles from ecMYC SCLC cell lines revealed features indicative of both metastasis and immunosuppression.<br /><br />The findings highlight the potential of targeting ecMYC for enhancing immunotherapy effectiveness in SCLC by mitigating the immunosuppressive microenvironment and the cancer's metastatic tendencies. Identifying MYC-paralog amplification as a biomarker could aid in tailoring more effective treatment strategies for SCLC patients who experience limited benefits from existing immunotherapy options.

Asset Subtitle

Jingwei Zhang

Meta Tag

Speaker Jingwei Zhang

Topic SCLC & Neuroendocrine Tumors

Keywords

extrachromosomal circular DNA

MYC-paralogs

small cell lung cancer

immunosuppressive tumor microenvironment

metastatic potential

immunotherapy

real-time PCR

RNA-sequencing

imaging mass cytometry

therapeutic targets