Subset of Cells in Bladder Cancer May Hinder Immunotherapy Outcomes

The presence of a type of cell — known to provide structure to one’s organs – found in bladder cancer may explain why some patients do not respond to PD-1 and PD-L1 immune checkpoint inhibitors, according to a study published in Nature Communications.

These checkpoint inhibitors are designed to enable the immune system to attack tumors; however, stromal cells — which are a subset of connective tissue cells often found in the tumor environment – may be preventing immune cells known as T-cells from seeking out and destroying the invading cancer.

In particular, Matthew D. Galsky, M.D., and colleagues used a cohort of patients with metastatic bladder cancer treated with Opdivo (nivolumab) and found that:

• The expression of a set of genes that are typically linked to more aggressive bladder cancers was actually more commonly linked to stromal cells rather than the cancer cells themselves.
• Tumors with increased expression of these genes, known as epithelial mesenchymal transition genes, did not respond well to immune checkpoint inhibitors.
• In these tumors, T cells were more likely to be separated from cancer cells by the stromal cells, which may mean stromal cells are hindering the ability of the immune cells to reach and eradicate the cancer cells.

CURE spoke with Galsky — who is a professor of medicine, hematology and medical oncology at Mount Sinai Hospital in New York City – about what these findings mean and what patients with bladder cancer should know moving forward.

CURE: How have immune checkpoint inhibitors changed the treatment landscape for bladder cancer?

Galsky: For a time period of approximately 30 years, there were no new drugs approved by the Food and Drug Administration (FDA) for the treatment of advanced bladder cancer and conventional chemotherapy was the only available treatment. Since 2015, there have been five PD-1/PD-L1 inhibitors approved for the treatment of advanced bladder cancer. These treatments have dramatically changed the outlook for a subset of patients by resulting in very prolonged control of cancer. Many of us in the field are searching for ways to extend this benefit to a large proportion of patients by seeking to understand why these treatments don’t work in some patients and do work in others.

In simple terms, can you explain what stromal cells are, and why they may be preventing T cells from attacking cancer?

Stromal cells are supporting cells for organs — the scaffold or cement, if you will, that helps to provide structure to an organ. Unlike scaffold or cement though, stromal cells are not passive players. In fact, they can be "activated" by neighboring cancer cells and start to behave badly, contributing to the growth and progression of cancer.

How were these cells related to PD-1 and PD-L1 inhibitor treatment outcomes?

We were interested in trying to determine the source of a set of genes that was associated with a poor prognosis in bladder cancer. Using a variety of techniques, we traced the source of expression of these genes to stromal cells much more so than the cancer cells themselves. We then showed that in bladder cancer specimens that are infiltrated with immune cells (that is, the body has developed an immune response against the cancer), increased expression of these genes that were emanating largely from stromal cells was associated with a much lower likelihood of benefit from immune checkpoint blockade.

We think that the stromal cells are either serving as a physical barrier (actually preventing the immune cells from reaching the cancer cells), a hypothesis which is supported by some work done by one of my colleagues using lung cancer models, or that the stromal cells are releasing substances that "stun" the immune cells and don’t allow them to function properly. Both of these mechanisms might actually be in play.

What does this mean for the bladder cancer treatment landscape?

We need to do two things to advance this work to have clinical impact. We need to be able to develop a test for tumor specimens to define which tumors are likely to have this particular mechanism of resistance to immune checkpoint blockade. We also need to better define why the stromal cells are impairing the activity of the immune cells, so we can develop combination treatments to overcome this resistance. We have ongoing projects focused on both of these areas.