ASH 2024 | Single-cell RNA-sequencing of 6 million tumor and immune cells from patients with MGUS and SMM

In this meeting, I’m presenting updated results from the single cell RNA sequencing study we have done on approximately 6 million tumor and immune cells, 877 samples, 533 bone marrow and peripheral blood specimens, 365 individuals with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, overt myeloma, as well as healthy donors. And so what we have found is that Granzyme B expressing cytotoxic T-cells, which are the most mature type of cytotoxic T-cell you can find in the immune system, increase in proportion from the MGUS to the myeloma stage. And this is because of increased clonal T-cell expansion as well as terminal differentiation of those clonally expanded T-cells. 

And based on what we know from solid malignancies, an increase in the proportion of Granzyme B expressing cytotoxic T-cells would normally be something to look forward to, something that would help better control the disease in these individuals. So it may seem counterintuitive that the increase in the proportion is a risk factor for progression in the context of myeloma, but what we show is that as the T-cells clonally expand and terminally differentiate, they also progressively lose their T-cell functionality. Not only that, but we take that one step further and show that high T-cell functionality has a transcriptional footprint on tumor cells, which upregulate genes that are important for immune evasion. And leveraging this transcriptional footprint, we have been able to validate the role of T-cell functionality as a risk factor of progression in two external cohorts, and so we think that this is really important because it confirms, if you will, the importance of this feature for prognostication and risk stratification of our patients. 

Now, in addition to that, we have developed our own algorithm for robust extraction of gene expression signatures from tumor cells and immune cells, and when we use that, we actually find several expression programs that change with progression from MGUS to myeloma, including, for example, cytokine programs in monocytes. We see a pro-inflammatory cytokine program increase with progression. This, of course, aligns really well with what we know from the literature in terms of increased neutrophil presence with disease progression and increased inflammation in patients with myeloma, but we also show a decreased expression of a cytokine program that we think is related to hypoxia, and again, this is in accordance with what we know about the role of hypoxia and disease progression in myeloma. 

On top of all of that, we also uncover an interferon stimulation program, which we show is active broadly within the bone marrow niche in lymphoid cells, myeloid cells, as well as tumor cells, and we show and validate in external cohorts that increased interferon stimulation is associated with a higher risk of progression. We also postulate that this may arise with the tumor cells, which we have shown before have the capacity to secrete type 1 interferon. Again, this is one of the perhaps counterintuitive findings, because in the solid cancer world, you know, interferon stimulation is thought to activate immune cells to battle tumor cells. But what we think is happening here is myeloma is a cancer of the immune system, and so likely, there are effects of interferon stimulation on plasma cells that perhaps we don’t understand yet very well. 

So we think the significance of this study is that it nominates immune biomarkers that we can sort of, maybe ushers, helps usher in an era where immune profiling can be used for risk stratification, but also for therapy selection. You can envision a future where patients with the highest T-cell functionality are the ones that, you know, maybe are selected for T-cell engager therapy or perhaps CAR T-cell treatment.

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