Trained immunity-promoting nanobiologics suppress tumor growth and potentiate checkpoint blockade immunotherapy
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ABSTRACT:
PROVIDER: PRJNA523329 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR12252435.fastq.gz | Fastqsanger.gz | |||
| SRR12252436.fastq.gz | Fastqsanger.gz | |||
| SRR12252437.fastq.gz | Fastqsanger.gz | |||
| SRR12252438.fastq.gz | Fastqsanger.gz | |||
| SRR12252439.fastq.gz | Fastqsanger.gz |
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Project description:We developed a nanobiologic platform that is designed to induce trained immunity. Through extensive in vitro screening, involving stability measurements and training assays on human and murine monocytes, as well as in vivo mouse biodistribution experiments, a bone marrow-avid nanobiologic lead candidate, named MTP10-HDL, was identified. MTP10-HDL’s 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-HDL’s 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.
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Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
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Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
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