Landscape of Molecular Events Regulating Multiple Myeloma Cell Responses to Natural Killer Cells

Gandolfi, Sara (2021). Landscape of Molecular Events Regulating Multiple Myeloma Cell Responses to Natural Killer Cells. PhD thesis The Open University.



Immunotherapy has remarkably changed the treatment paradigm in hematologic malignancies and natural killer (NK) cell therapy represents an attractive option. However, there have been, to our knowledge, no genome-wide CRISPR-based screens to identify
candidate markers of response to NK cells in multiple myeloma (MM), which remains incurable. Furthermore, the molecular markers determining cancer cell resistance to NK cells, especially in the context of tumor interaction with the bone marrow (BM) stromal microenvironment remain incompletely understood but have major translational relevance. In this study we sought to address this void by applying genome-scale loss of-function and gain-of-function CRISPR-based screens in MM cell lines to interrogate the markers of cancer cell resistance at a functional level. The data showed that NK cell response of MM cells is modulated by activation of several metabolic and homeostatic genes, receptor kinases, and membrane-bound proteins of the mucin family, while genes whose LOF or GOF is associated with worse clinical outcome seemed not to impact the response. We then integrated such data with those obtained by quantifying the NK cell responsiveness of 70 molecularly annotated hematologic cancer cell lines, in presence or in absence of BM stromal cells. Two distinct clusters of cell lines were identified, sensitive and resistant to NK cells, which showed an overall markedly decreased responsiveness in presence of stroma, while retaining their distinct clustering. RNA-seq data showed no differentially expressed genes at baseline clearly allowing to predict NK cell response. However, the two clusters differed at a pathway level, with an enrichment of PI3K-AKT, TNFR2, HDAC class I gene signatures and the antigen presentation machinery genes in the resistant cluster, consistent with data from LOF CRISPR studies. Overall, this study provides a comprehensive landscape of the mechanisms regulating MM cells response to NK cells, with translational implications for future biomarker-oriented applications of NK cell-based adoptive therapies.

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