PLX277678

GSE126793: Trained immunity-promoting nanobiologics suppress tumor growth and potentiate checkpoint blockade immunotherapy

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

We developed a nanobiologic platform that is designed to induce trained immunity. Through extensivein vitroscreening, involving stability measurements and training assays on human and murine monocytes, as well asin vivomouse biodistribution experiments, a bone marrow-avid nanobiologic lead candidate, named MTP10-HDL, was identified. MTP10-HDLs potent anti-tumor capabilities were established in a dose response study. We found that these anti-tumor effects are the result of trained immunity-induced myelopoiesis, caused by the activation of hematopoietic stem cells and multipotent progenitors in the bone marrow. Moreover, we established that MTP10-HDL treatment overcomes the immunosuppressive tumor microenvironment (TME) by reducing the number of myeloid-derived suppressor cells and tumor associated macrophages. The immunologically rebalanced TME potentiated concurrent checkpoint blockade therapy, resulting in augmented anti-tumor efficacy. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response, as a monotherapy or in combination with checkpoint blockade.; We examined MTP10-HDLs effect on hematopoiesis to elucidate the mechanism underlying its anti-tumor effect in C57BL/6 mice without tumors. We performed RNA sequencing (RNA-seq) to investigate HSC activation. Bone marrow from treated and untreated mice was harvested and the HSCs were isolated by flow sorting. SOURCE: Lisa Willemsen (l.willemsen@amc.nl) - Amsterdam UMC - Location AMC