Examining the Role of Blocking STAT3 in AML

Marcin Kortylewski, PhD, a professor in the Department of Immuno-Oncology at the City of Hope Comprehensive Cancer Center, discusses some of the goals and findings of his research on blocking STAT3 in acute myeloid leukemia (AML) cells.

According to Kortylewski, it can be difficult to target the genetics of leukemia cells as their background is diverse. Due to AML always progressing and being very heterogeneous, a molecule targeting STAT3 in AML cells was developed.

His research aimed to look at gene expression and gene reprogramming of transcriptional events using RNA sequencing to examine the changes found from deletion and activation for AML cells. What Kortylewski found was that a rapid regression in leukemia was linked to blocking STAT3 in these AML cells, caused by immune mediated circulating tumor DNA responses.

Transcription:

0:08 | We wanted to know what is the mechanism of action of this strategy? Was it actually driving immune responses? It turned out that when we looked at the leukemic cells, and we showed in this presentation, leukemic cells were undergoing very dramatic change. When we isolated them from mice, we could take a look at using electron microscopy, finding the subcell structure completely changed. We have observed differentiation of these leukemic cells into a macrophage-like phenotype. Initially, we could speculate whether it's a macrophage monostatic or gnotobiotic phenol type, but we have basically confirmed this data later using a gene expression study.

0:59 | In about 10% of leukemic cells, these changes cause their differentiation, and they tend to gain the ability to present the antigen. These cells, which were originally leukemia and have markers of leukemic cells, also express GFP, so we can track them. They become GFP positive antigen presenting cells, which is really interesting. This affects about 10-15% of leukemic cells in mice, but this is enough of the pool of antigen presenting cells to induce anti-tumor immune responses.

1:37 | We decided to dig deeper into a gene expression and gene reprogramming of transcriptional events in those myeloid cells using RNA sequencing analysis and looking at changes that are caused by a start with deletion, as well as by triggering activation of this receptor TLR9 that we use as a gateway into those cells, and by a combination of those 2 effects. What was really interesting was that RNA sequencing data has basically shown us that neither of these effects alone, so TLR9 activation nor STAT3 deletion alone, had the same effect as a combination of these 2 effects.

2:29 | It seemed like a STAT3 elimination by silencing or by using a molecule was able to trigger dramatic reprogramming of the cells from leukemic cells into a macrophage-like phenotype that have been confirmed at the gene expression level by their activity and ability to phagocyte different molecules creating a population of differentiated cells with expression of IRF8 or CDP-alpha and decreased expression of transcription factors which are normally found in leukemia, such as RUNX1. These changes seem to be a driver of immune activation that we see in this model.