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Targeting myeloid-derived suppressor cells (MDSCs) has become a promising area of cancer research, with a goal toward improving the efficacy of immunotherapies. At the recent virtual two abstracts were presented that showcased the encouraging anti-tumor potential of targeting MDSCs in advanced disease.

In this exclusive 番茄社区 video, , of the Norris Comprehensive Cancer Center at the University of Southern California, breaks down the data from the two studies and describes to better understand the mechanism of response in metastatic breast cancer.

Following is a transcript of her remarks:

Hi, my name is Dr. Evanthia Roussos Torres. I am a medical oncologist at University of Southern California with the Norris Comprehensive Cancer Center. I'm delighted to be here today to discuss a really interesting topic that was covered in some of the research abstracts at ASCO. And that is looking at the role of myeloid-derived suppressor cells in the tumor immune microenvironment and how they may play a role in combination therapies with checkpoint inhibition and other immunotherapies to improve response rates in traditionally cold or non-immunogenic tumors.

I wanted to start off by highlighting two abstracts that are very relevant to this topic. I wanted to start off first talking about which has really focused on the importance of targeting myeloid-derived suppressor cells to alter T-cell response in a really novel way. Her abstract and poster discusses the engineered CAR-T that leads to a myeloid-derived suppressor cell (MDSC) apoptosis and CAR-T co-stimulation that promotes T-cell persistence and expansion. So this is a really interesting strategy as it's one of the first CAR-Ts that are looking to alter this type of suppressor immune cell. And I think the importance of remodeling the tumor microenvironment in a way that ultra suppression has a lot of potential.

So just to give you a little bit of background about what are these myeloid-derived suppressor cells and why should we even care about them in the context of immunotherapy? So typically, and traditionally, immunotherapy is really focused on T-cell response, and we've had the most success in the medical oncology world targeting T cells in melanoma and in non-small cell lung cancer. And in some of the tumor types that have been less responsive, what we have found is actually that the tumor immune microenvironment is really infiltrated with a lot of suppressor cells. And one of the types of these suppressor cells are called the myeloid-derived suppressor cells, MDSCs. And so there's a lot of different groups trying to understand what are these suppressor cells, what do they do?

And what I really found very exciting and interesting about Dr. Hoyos Velez's work and some of, really the novelty in what she's doing is to try and target these cells, like primarily, as a way to really alter that response to checkpoint inhibition or in this case CAR-Ts. To be able to improve T-cell response by first eliminating a suppressor response.

And so I think that that's why this is so novel because in these other tumor types, you don't really have to do that. You don't have to get rid of those suppressor cells first. You can kind of just go right in and just try to improve activation of your T cells or improve infiltration. But in breast cancer and pancreas cancer, and many other of these types of solid tumors that don't have as much success with immunotherapy, it really seems that you have to do something else to alter that tumor microenvironment first and specifically the suppressor microenvironment to really get a robust response.

And so that brings me to , which is the second abstract I wanted to highlight, is that they are similarly targeting MDSCs and this is through a different mechanism by targeting a CD11b molecule that's expressed on MDSCs and tumor-associated macrophages. And they're highlighting the work of a phase I trial that has a compound that they combined with pembrolizumab [Keytruda], an anti-PD-1 inhibitor. And the interesting aspect of this compound is that it's acting to shift the immature myeloid cells, those MDSCs into pro-immune macrophages.

And again, to provide a little bit more background, the world of MDSCs is controversial in that this is an immature immune cell population that's very plastic, and it's known to differentiate into different immune cell types depending on the surrounding microenvironment. So to use a compound that promotes differentiation is also very intriguing because you're really looking to alter the surrounding suppressor cells into something that actually supports an immune response, which is what we're trying to do with checkpoint inhibition and in this particular case in combination with pembrolizumab.

So I think, again, the strategy is the same in that it's targeting the suppressive cell population. The difference here is that it's not actually just trying to eliminate the suppressive signaling, but actually trying to promote differentiation into something that would support a T-cell response. And instead of getting rid of those suppressor cells, they can actually mature into something that also has an anti-tumor response.

So this is all really exciting to me because this is what my lab actually studies. So I have a lab that studies primarily breast cancer, but I've also done some work in colon and pancreas. And in the work that I've done, I was looking at combination therapies with a histone deacetylase inhibitors, specifically entinostat in combination with nivolumab [Opdivo] and ipilimumab [Yervoy], anti-PD-1 and anti-CTLA-4. And in the preclinical work that my lab has done we actually found that one of the main reasons we see an improved response to those checkpoint inhibitors in breast and pancreas cancer is because we alter the suppressive capabilities of these MDSCs.

And so I've spent a lot of time really trying to understand the mechanism of response. How is it that the HDAC inhibitor entinostat -- and there are other compounds known to do this as well -- how is it that they change this suppressive signaling of these cells and how does that then lead to improved response to checkpoint inhibition? And the whole point of this is to understand how we can actually more specifically target these cells to combine them with checkpoint inhibition and get better response rates in these tumor types that typically don't respond. And ultimately to bring novel combination therapies to patients who currently don't benefit as much from this really powerful and exciting class of drugs, which are immunotherapy checkpoint inhibitors, as well as CAR-T therapy.

So when I see the work in the two abstracts, I highlighted it really hits home for me because this is what this is what I'm working to do. And understanding the signaling mechanisms within specifically the MDSCs, but also in tumor-associated macrophages, is one really promising strategy to try and get therapeutic combinations that really have a chance in tumor types that haven't typically shown high response rates.

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