Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, due to the lack of diagnostic/prognostic biomarkers and effective therapies. While immune checkpoint inhibitors (ICIs) like anti-PD-L1 antibodies offer potential benefits, majority of patients do not respond to therapy and remain at high risk of adverse effects. PD-L1 expression, assessed through immunohistochemistry, is currently the only FDA-approved biomarker for guiding ICI therapy but, it is not considered a perfect biomarker due to numerous technical discrepancies and limited knowledge on the regulation of its expression, thus implying a complex regulation of PD-L1 expression in tumor cells, and emphasizing the need to better understand PD-L1 regulation in NSCLC. Our recent findings suggest that microRNAs (miRNAs) may significantly influence PD-L1 expression by directly binding to its messenger RNA or indirectly modulating genes that regulate PD-L1. Previously, we also identified a novel miRNA signature predictive of chemotherapy response in NSCLC, associated with high PD-L1 expression and active IFN-γ response, thus indicating a critical role for miRNAs in PD-L1 regulation in advanced NSCLC. Therefore, this project aims to launch an in-depth investigation of miRNA-mediated molecular mechanisms that regulate PD-L1 expression in NSCLC by identifying miRNAs as well as the target genes and pathways they utilise to regulate PD-L1, and the effects of miRNA-mediated PD-L1 regulation on immunotherapy response in NSCLC. Expected outcomes include the identification of an ex-vivo miRNA signature linked to PD-L1 expression, a comprehensive understanding of miRNA roles in PD-L1 regulation, and novel insights into the complex regulation of PD-L1 in lung cancer. Consequently, this study will significantly enhance the understanding of PD-L1 regulation, and facilitate the discovery of reliable biomarkers for predicting immunotherapy response in cancer patients.
Afanga, M., Cuttano, R., Bianchi, F. (2024). Dissecting the role of microRNAs in the regulation of the PD-L1 immune checkpoint in lung cancer. In 64th annual Meeting of the Italian Cancer Society. Science-driven approaches to achieve early diagnosis of cancer and to overcome therapy.
Dissecting the role of microRNAs in the regulation of the PD-L1 immune checkpoint in lung cancer
Afanga Miriam Kuku;
2024
Abstract
Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, due to the lack of diagnostic/prognostic biomarkers and effective therapies. While immune checkpoint inhibitors (ICIs) like anti-PD-L1 antibodies offer potential benefits, majority of patients do not respond to therapy and remain at high risk of adverse effects. PD-L1 expression, assessed through immunohistochemistry, is currently the only FDA-approved biomarker for guiding ICI therapy but, it is not considered a perfect biomarker due to numerous technical discrepancies and limited knowledge on the regulation of its expression, thus implying a complex regulation of PD-L1 expression in tumor cells, and emphasizing the need to better understand PD-L1 regulation in NSCLC. Our recent findings suggest that microRNAs (miRNAs) may significantly influence PD-L1 expression by directly binding to its messenger RNA or indirectly modulating genes that regulate PD-L1. Previously, we also identified a novel miRNA signature predictive of chemotherapy response in NSCLC, associated with high PD-L1 expression and active IFN-γ response, thus indicating a critical role for miRNAs in PD-L1 regulation in advanced NSCLC. Therefore, this project aims to launch an in-depth investigation of miRNA-mediated molecular mechanisms that regulate PD-L1 expression in NSCLC by identifying miRNAs as well as the target genes and pathways they utilise to regulate PD-L1, and the effects of miRNA-mediated PD-L1 regulation on immunotherapy response in NSCLC. Expected outcomes include the identification of an ex-vivo miRNA signature linked to PD-L1 expression, a comprehensive understanding of miRNA roles in PD-L1 regulation, and novel insights into the complex regulation of PD-L1 in lung cancer. Consequently, this study will significantly enhance the understanding of PD-L1 regulation, and facilitate the discovery of reliable biomarkers for predicting immunotherapy response in cancer patients.
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