Lingtao Jin, PhD

Lingtao Jin, PhD

Institution: University of Florida

Project: Targeting Protein to Overcome Immunotherapy Resistance in Small Cell Lung Cancer

Grant(s): Innovation Award

We have investigated the role of platinum-induced metabolic reprograming in regulating tumor microenviroment in small cell lung cancer. Untargeted metabolomic analysis revealed that glutamine metabolism activity is significantly higher in platinum-resistant small cell lung cancer cells. Also, acute exposure of small cell lung cancer cells cells with platinum also increased glutamine uptake, but etoposide did not. Collectively, these data revealed the enhanced glutamine metabolism in small cell lung cancer cells in response to platinum. RNA sequencing analysis further showed that fatty acid metabolism pathway is highly enriched in cisplatin resistant small cell lung cancer cells, suggesting small cell lung cancer cells boost the glutamine metabolism in response to platinum, which, as a result, leads to enhanced lipid synthesis from glutamine. We therefore hypothesized that the platinum-induced enhancement of lipid synthesis in small cell lung cancer cells may reshape the lipids profile of tumor-derived exosomes which, as fatty acids carrier, may affect immune cells in the tumor microenvironment such as dendritic cells. Indeed, we uncovered that platinum, through tumor-derived exosomes, impacts the crosstalk between cancer cells and dendritic cells in vitro and in vivo. We first isolated tumor-derived exosomes from small cell lung cancer cells. Indeed, platinum greatly boosted tumor-derived exosomes’ ability to induce lipid accumulation and dysfunction of dendritic cells in vitro, which can be reversed by inhibition of glutamine metabolism. Furthermore, we examined whether platinum increases the ability of tumor-derived exosomes to induce dendritic cell lipid accumulation and dysfunction in vivo. By using GFP-CD9-small cell lung cancer cells to trace tumor-derived exosomes in vivo, we found that platinum induces lipid accumulation and dendritic cell dysfunction in tumor-infiltrating dendritic cells that actively take up tumor-derived exosomes but not in tumor-infiltrating dendritic cells that do not actively take up tumor-derived exosomes, suggesting that platinum enhances the ability of tumor-derived exosomes to negatively affect dendritic cell functions in vivo. We will continue to delineate the potential crosstalk between tumor cells and tumor immune microenvironment. Importantly, we will evaluate targeting this crosstalk to improve platinum-immunotherapy combination in small cell lung cancer.

Update: We have investigated the role of platinum-induced metabolic reprograming in regulating tumor-derived exosomes in cancer. We uncovered that platinum, through tumor-derived exosomes, impacts the crosstalk between cancer cells and dendritic cells. Specifically, platinum induces lipid reprograming in cancer cells, thereby enhancing the ability of tumor-derived exosomes to negatively affect dendritic cell functions. We will continue to delineate the potential crosstalk between tumor cells and tumor immune microenvironment. Such crosstalk may significantly modulate anti-tumor immunity and the efficacy of anti-tumor immunotherapy.

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