ASH 2025 | Investigating the role of CD48 in the regulation of NK-cell immunity in multiple myeloma

With that project, it’s very different. So essentially there, what we’re really trying to look at is this concept in multiple myeloma. We’ve now had many studies that really explore how myeloma, as it progresses from those very earliest malignant clones into full-blown clinical myeloma, how it interacts with the immune microenvironment within the bone marrow. And so one of the big questions we’re trying to address here, we have previously identified there’s a protein called CD48, one of these surface proteins in multiple myeloma. It’s one of the most abundant. So basically, if you have a myeloma tumor cell, you think about there are many thousands of different proteins on the surface. CD48 is one we found to be one that’s one of the most common at the cell surface. And the question is, what’s it doing there? 

What we had found, and others had noticed as well, was that in some of the high-risk subgroups of multiple myeloma, so say gain 1p, t(4;14), we noticed that CD48 expression was higher, and we know these patients have worse outcomes. But other data had shown that CD48 is important in NK cell biology. There are natural killer cells. These are cells that we found, others have also demonstrated, to become dysfunctional in multiple myeloma. And we know CD48 can potentially turn on these natural killer cells and help them kill the tumor cells better. But also, if you have too much CD48, it may make them kill worse over time. 

And so what we tried to do is we explored and we used a multitude of different technologies. We used both large-scale genome-wide CRISPR interference and activation screens, or excuse me, CRISPR knockout and activation screening in collaboration with Constantine Mitsiades. We analyzed single-cell data from multiple myeloma patients. We also took tumor cells that are murine, a mouse model of multiple myeloma, and actually overexpressed and knocked out CD48. And essentially what we found was that CD48 is important in actually driving that NK-cell killing of multiple myeloma. But even high expression of CD48 can’t avoid this dysfunction of NK-cells, basically. So we couldn’t tell whether it’s the key driver of that dysfunction. We still need more work to figure that out. But what we do believe potentially is that by modulating CD48 and potentially increasing its abundance early in the multiple myeloma course, we may help NK-cells do a better job of killing myeloma and maybe help slow its progression to some degree. So that’s really where we need to go, but it’s a very biological story.

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