Cancer, COVID-19, and the Immune Genome with Dr. Brian Brown

CRI Technology Impact Award recipient Brian D. Brown, PhD, of the Icahn School of Medicine at Mt. Sinai in New York City, has been developing a technology to help us better understand how cancer and the immune system interact. Specifically, he’s defining how different genes affect cancer cells’ sensitivity to being detected and eliminated by the immune system.

In many ways, the immune system responds similarly to both cancer cells and cells infected by viruses, so some of these genes may also play a role in the immune system’s response against cells infected by the novel SARS-CoV-2 coronavirus that causes COVID-19. We caught up with Dr. Brown recently to learn about his progress on both fronts.

Miriam Merad, MD, PhD; Sacha Gnjatic, PhD; Brian D. Brown, PhD; Joshua D. Brody, MD Photo courtesy of Brian Brown

Arthur N. Brodsky, PhD:

Hi, Dr. Brown, thanks for taking the time to speak with us. So, in the context of cancer, how does your technology work and how do you hope it might help overcome current limitations in terms of cell analysis?

Brian D. Brown, PhD:

Traditionally, we have done these types of genetic studies one by one, but with 20,000 genes in the human genome, there hasn’t been a way to do this quickly or cost-effectively.

To figure out what a gene does, you can remove it from a cell and ask, “What happens to the system?” In the context of cancer immunology, we can knock out a gene like the one that codes for PD-L1—which we now know enables cancer cells to shut down cancer-targeting T cells—and see what changes. If your tumor shrinks, that tells you that PD-L1 must be important for allowing the tumor’s growth. But PD-L1 expression, like all immune-related processes, is influenced by many other genes as well, and to investigate them one by one with respect to their various potential roles would be a very slow process when hundreds or thousands of possible genes might be involved.

Over the past ten years, there have been efforts to try and scale that up. We’ve been focused on that, too, and now the technology we’ve developed with CRI’s support enables us to remove—or mutate in a specific way—hundreds of genes simultaneously. And we can still study them in the same detailed manner as if we were doing them one by one.

This enables us to really start to analyze what we call the cancer immune genome—at least from the perspective of the cancer cell—which are the genes that influence whether or not cancer cells are detected and eliminated by immune cells. The gene for PD-L1 is an example, but it’s about more than individual genes. Even PD-L1 is just one protein in a vast network of proteins involved in communication between cancer cells and immune cells. Now we can analyze the many components of that network with speed and efficiency.

Arthur N. Brodsky, PhD:

Initially, you’re using this technology to look at breast cancer cell genes induced by interferon gamma. What role does the interferon gamma signaling pathway play in immune responses here?

Brian D. Brown, PhD:

Interferon gamma is a molecule that gets expressed by activated T cells and plays a central role in interactions between cancer and the immune system, particularly in the context of the immunoediting theory developed by Dr. Robert Schreiber at Washington University in St. Louis. More recently, scientists like Antoni Ribas at UCLA and Pam Sharma at MD Anderson have provided insights into interferon gamma’s role in both responses and resistance to PD-1/PD-L1 checkpoint immunotherapy. Particularly, they found mutations in the JAK/STAT pathway, which is just downstream of interferon gamma in the signaling cascade and is critical for T cells to kill cancer cells.

So, what exactly is interferon gamma doing to the cancer cells that makes it important? Once it binds to its receptor on the cancer cell’s surface, it triggers activity in a lot of other genes that are now either turned on or silenced in the cancer cells. In addition to PD-L1, interferon gamma also induces production of an important cell surface system called the major histocompatibility complex, or MHC, which enables T cells to recognize cancer cells. This sounds counterintuitive, that it triggers one gene that helps cancer and another that enables its elimination, but it’s part of the immune system’s finely tuned balance that normally serves us well in most situations to prevent over or under reacting to a threat.

There are over 200 other genes that are also upregulated in response to interferon gamma, but whose function we don’t yet know. Some may be pro-tumor, but some will improve the immune system’s cancer-fighting capabilities. Knowledge of both will likely be important for us to maximize the potential of immunotherapy for patients.

Arthur N. Brodsky, PhD:

Another factor you’ve mentioned is that, among these many genes, there may be a good amount that are redundant, as in they are kind of indirect players or messengers that aren’t always required for a particular cancer cell behavior that they’re correlated with. On the contrary, some pathways might serve as indispensable nodes in the network. Will your technology eventually aid efforts to determine the relative importance of these individual genetic components, too?

Brian D. Brown, PhD:

We are hopeful. Identifying genes where there is redundancy or cooperation is a widespread goal in the cancer field because of its potential to guide the development of future immunotherapies by identifying the best targets for therapy.

With respect to scaling this up to systematically search for targets, everyone wants to be able to look at every combination of dozens of different genes. But first we need to be able to do two or three at a time, and that’s what we hope this technology will be able to do. That’s really where a lot of work needs to be done because as soon as you start to build these networks it quickly become intractable.

Brian D. Brown, PhD; Joshua D. Brody, MD; Miriam Merad, MD, PhD Photo courtesy of Brian Brown

Arthur N. Brodsky, PhD:

In addition to redundant genes serving the same purpose, there are also synergistic genes whose combined activity, or inactivity, can amplify certain biological effects. Are you exploring these potential pathway synergies in order to uncover information that might be used to improve care with existing treatments as well as the design of novel immunotherapies?

Brian D. Brown, PhD:

Absolutely. A great example of this concept involves olaparib, a PARP inhibitor that targets a DNA repair pathway and is used to treat ovarian cancer. This drug isn’t thought to affect normal cells, which have other functional DNA repair pathways they can rely on. In cancer cells with mutations in other DNA repair pathways, this drug’s ability to knock out another pathway at the same time gives you this profound effect.

That's exciting for cancer biology because if you can find a cancer cell with a genetic mutation not found in normal cells, you can think about using drugs to target complementary pathways and only impact cancer cells. This should make them safer for patients, too.

We are always looking for these types of opportunities where cancer-specific mutations might amplify the effects of a certain treatment. On the contrary, the presence of some mutations might indicate that a certain treatment is unlikely to work in some patients. With respect to PD-1/PD-L1 checkpoint immunotherapies, for example, mutations in the gene for beta-2-microglobulin, which is involved in the MHC system I mentioned earlier, have been linked to resistance to checkpoint immunotherapy, and patients whose tumors possess them are unlikely to respond.

Arthur N. Brodsky, PhD:

You’ve outlined how you’re using this technology in cancer cells, to see how their genes affect cancer-immune interactions. Do you have any plans to use this technology to look at things from the perspective of T cells?

Brian D. Brown, PhD:

Yes, that work is already under way actually. We have been using the technology with T cells as well as the bone marrow stem cells that give rise to all immune cells. We have a big project, which is now on hold due to the COVID-19 pandemic, where we’re going to knock out genes in T cells and determine which ones affect T cell exhaustion. Moving forward, we also plan to apply this technology to enable easier determination of the immune composition within tumors, which is one of the best indicators of whether a person will respond or not respond to immunotherapy.

In the current moment, we’re also planning to leverage this technology to better understand the genes that influence how immune cells respond to the novel SARS-CoV-2 coronavirus. In particular, we want to find out which genes are involved with cytokine release syndrome, an excessive inflammatory response that has been associated with deaths caused by COVID-19, as well as those genes that are interacting with the virus to facilitate or restrict its spread. Hopefully, this might help us understand susceptibilities to the disease and potentially provide therapeutic targets.

Coronavirus binding to receptors. Photo: Juan Gaertner, Science Photo Library

Arthur N. Brodsky, PhD:

How important has CRI’s support been in your efforts, both those against cancer and COVID-19?

Brian D. Brown, PhD:

The technologies we are developing with CRI’s support are precisely the tools we need to find the genes that are involved in COVID-19 disease.  We are continuing to develop new variants of the technology, including a version that can be resolved with tissue-level spatial resolution, which will help us better understand how SARS-CoV-2 spreads and affects the local immune response within the infected tissue.

Arthur N. Brodsky, PhD:

Can you talk a little bit about what it’s been like being so close to the front lines of efforts against the pandemic in a New York City hospital system?

Brian D. Brown, PhD:

Well, I’d like to commend the job done by everyone here at Mt. Sinai. It’s really heroic what our doctors, nurses, scientists, and leadership have been trying to do. In particular, Dr. Miriam Merad, who leads our immunology group and won CRI’s Coley Award in 2018, deserves a lot of credit.

She started this massive initiative to deeply understand the immune system’s role in COVID-19. Samples from thousands of patients are being taken from our hospital and brought back here to the lab. With these samples, we're doing extensive immune monitoring, looking at levels of antibodies, cytokines, and other important biomarkers in order to understand the various immune cell types that might respond against the virus. Then we might be able to start doing studies to identify the causes of severe disease. We're clearly seeing that there can be wild variations from person to person, and these studies might help us explain why only some people get severely ill.

Brian D. Brown, PhD; Joshua D. Brody, MD; Miriam Merad, MD, PhD at Mt Sinai. Photo courtesy of Brian Brown

All of this is an incredible amount of work. We have shifts working night and day collecting samples from patients and health care workers, and a whole operation of volunteers just spend hours labeling tubes for the collection team. I don't know what stories will get written up in the history of this, but I can tell you that there are unbelievable and selfless acts being performed by many people at this institute.

I’ll end by saying this. The COVID-19 pandemic has been a terrible tragedy. I wish we already had a way to better treat the disease. Even though we don’t yet, I am optimistic we will soon, and that’s thanks to investments that organizations like CRI have made in basic and translational immunology over the years. Our understanding of processes like cytokine release syndrome, the application of technologies for human immune monitoring, and improvements in vaccine development—all are being put toward improving treatment for COVID-19.

Arthur N. Brodsky, PhD:

Thank you for all that you are doing, and stay safe Dr. Brown!

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