2018 PCRP Investigator Vignette

Title: A Relationship Between Mast Cells and Racial Disparity of Prostate Cancer

Investigator: Karen Sfanos, PhD; Johns Hopkins University

My research is under the underlying theme that we think that inflammation is important in prostate cancer development and progression, and we’re really trying to understand what the immune cell component is in the tumor microenvironment in prostate cancer and if it can be used to predict prostate cancer aggressiveness.

So what we know in African Americans is that they have a more aggressive form of prostate cancer. Another thing that we know is that the typical genetic alterations that seem to track with more aggressive disease are actually underrepresented in tumors from African American men. So there must be something else that’s contributing to this more aggressive disease course.

And what we saw in multiple studies looking at RNA expression in tumors from African American men versus white men is an overrepresentation of genes that are involved in inflammatory pathways and, specifically, genes that are expressed by innate immune cells, things like mast cells and macrophages.

So is there a differential presence of these types of cells in the tumor microenvironment of tumors in African American men versus white men? And that was really the rationale for starting this study.

This poster is really focused down on one cell type, which is mast cells.

So what is shown here is the development of image analysis software for automated quantification of the number of mast cells in tissue micro-array spots. So what you’re seeing here in brown is an immuno-stain for cytokeratin 8, so it stains all of the epithelial cells. And then, in red, is mast cell tryptase; so all of the red spots are mast cells. And what the computer software does is it goes in and identifies and quantifies the area of total tissue and then it can count—I don’t know if you can see the little mast cells here with the green arrows on them—it can count the number of mast cells. So we can automatically count mast cells in a large number of TMA spots in different TMA cohorts.

We started out asking the question, just in general, does the number of mast cells seem to track with disease aggressiveness? And we measured that by using a tissue microarray of 500-plus men that have been treated at the Johns Hopkins Hospital that had recurrence after prostatectomy matched to men who had not a recurrence at the time that their matched case had recurred. And what we found was that the men that had very low numbers of mast cells in their tumor are also the men that are more likely to recur.

And this was a little bit surprising to us is that, if there are fewer mast cells in the tumor, the man was more likely to recur. And then, in addition to that, we found the absolute opposite association in the matched benign tissues. Higher numbers of mast cells were more associated with men that ended up recurring than men that did not.

And down here is just an image that kind of reiterates what I just said, where you’re looking at two different tumors. They have the same Gleason score. They have the same amount of stroma. They have the same amount of epithelium, but the tumor over here on the right has a lot more mast cells than the tumor on the left. And what we found is that this tumor on the left that has lower numbers of mast cells was more likely to recur.

The next step was to look at this in relation to racial disparities because we know African American men also tend to do worse in terms of prostate cancer outcomes.

So we looked at two different race disparities, TMA sets, one of which we obtained from the Prostate Cancer Biorepository Network, which is also a PCRP-funded network, and they have a TMA of 150 cases, 75 African American men matched to 75 white men with prostate cancer, that are matched on tumor grade and stage. And then we also looked at a separate TMA set that we worked on in collaboration with Dr. Tamara Lotan, with 140 African American and 151 white men again that were matched on similar tumor grades and stages.

And what we’ve found, again, in the tumor, regardless of tumor grade, African American men seem to have lower numbers of mast cells in their tumor. And we saw that in both TMA sets. Interestingly, they also had lower numbers of mast cells in the benign tissue.

And down here, what I show is that, if you stratify it out by risk group, again, the African American tumor, lower number of mast cells, even especially in the intermediate risk group and also, in the white men, the high-risk group had a lower number of mast cells in the tumor.

So, in conclusion, we find this very interesting that, in both of the TMA sets that we looked at, one focusing on PSA progression and the other one focusing on racial disparities, we seem to find a similar theme, and that low intratumoral mast cells seem to (a) associate with PSA progression; but then also that, in general, it seems like the tumors of African American men have fewer of these types of cells, and that could potentially—we need to do further study—but it could potentially be one of the reasons why there’s this disproportionate worse outcome in African American men.