Friday, May 3, 2024
5/3/2024
PROBLEM. Pediatric tumors represent a very heavy social and economic burden with profound emotional involvement not only for the directly affected children but also for their family and friends. Within pediatric tumors, neuroblastoma (NB) is of particular relevance, since it is the most common solid cancer in children outside of the skull and it still kills about 40% of patients diagnosed with the most aggressive forms. Therefore, there is a clear need to improve the treatment for this deadly disease. Development of more potent immunotherapies could improve outcome for these patients. PREMISE. Natural killer (NK) cells, especially when “activated” (aNK cells) mediate direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). All cell types release extracellular vesicles called exosomes that contain biologically active components (proteins, DNA, mRNA, and non-coding RNAs including miRs) that can be delivered to recipient cells and influence their functions. Exosomes released by aNK cells, could increase the efficacy of chemoimmunotherapy in NB. Little is known about human aNK cell-derived exosomes, their therapeutic potential and role as biomarkers of response to chemoimmunotherapy in NB. Our group was the first to show that microRNAs (miRs) in aNK-derived exosomes are able to kill NB cells. OUR DATA. We can propagate and activate blood NK cells from normal donors and patients with NB using K562-mbIL21 artificial antigen presenting cells (aAPC) plus IL-2. We discovered that these aNK cells release large quantities of exosomes and that purified aNK exosomes are cytotoxic for NB cell lines. We also have preliminary evidence that aNK-derived exosomes contain miRs that contribute to the cytotoxic effect of aNK-exosomes. We also observed that children affected by NB responsive to chemoimmunotherapy, present markers of aNK activation in their blood. We hypothesize that aNK-derived exosomes kill NB cells through the exosomal transfer of MYCN-, AURKA-, TGFBR1- and TGFBR2-targeting miRs, and that these miRs can be exploited to develop an anti-tumor effect and implement the efficacy of chemoimmunotherapy for NB patients. We also hypothesize that specific circulating and exosomal miRs can be exploited as biomarkers of response to chemoimmunotherapy in children affected by NB. These hypotheses will be tested in the following Specific Aims: 1) To study cytotoxicity mechanisms and therapeutic efficacy of aNK- derived exosomes alone and combined with chemoimmunotherapy in NB; 2) To assess association of NK- exosomal miRs, circulating RNAs, and gene expression profiles with response in patients treated on chemoimmunotherapy regimens. SUMMARY. We focus upon a completely new immunotherapeutic strategy using human miR-enriched aNK exosomes. The results of this study will provide important information for producing highly cytotoxic aNK exosomes which could potentiate efficacy of existing chemoimmunotherapy. This study will also identify new exosomal RNA cargo able to stratify neuroblastoma patients for response to chemoimmunotherapy.
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