Understanding the Role of Mononuclear Phagocytes in the Tumor Microenvironment

Malay Haldar, MBBS, PhD, assistant professor in the Department of Pathology at the University of Pennsylvania, talks with Pharmacy Times about all things mononuclear phagocytes, including their role in the tumor microenvironment, novel subsets, and how targeting them can be an effective immunotherapy treatment for cancer patients.

Q: To offer context, could you please describe the mononuclear phagocyte system? (The tumor microenvironment?)

Malay Haldar, MBBS, PhD: The immune system has specialized divisions, or departments, so to speak. There are cells whose main job is to detect threats and distinguish it from normal cells, and these threats could be pathogens or cancer cells. And then there are cells that specialize in killing or neutralize these threats.As you know, T cells are quite good at killing cancer cells, but then T cells need instructions regarding which cells to kill. Without this information, T cells will not be mobilized against the threat- or worse, might end up killing or damaging normal cells.

So mononuclear phagocytes a group of immune cells that exist in our tissues. Their main function is to constantly monitor their environment for the potential presence of danger or threats. And once they detect something that is what they perceive as a threat, they will convey this information to T cells and help mobilize T cells against that specific threat.

So, these phagocytes are really important to initiate and regulate an immune response, including an anti-tumor immune response. And they’re not a single entity. So mononuclear phagocytes are not one type of cell, they are comprised of three main types of cells: monocytes, macrophages, and dendritic cells. Actually, the majority of the monocytes would end up giving rise to macrophages and dendritic cells. By themselves, they do not play as important of a role in threat detection as the other two. So that's a very simple overview of the mononuclear phagocytic system.

And then, like I said, they're often known by different names. You can call them antigen presenting cells, MLR antigen presenting cells, monocytes, macrophages, DCs, etc. And if you consider tumor microenvironment, which obviously comprises of tumor cells and various types of immune cells, mononuclear phagocytes are an important component of the of the tumor microenvironment. Where, like I mentioned before, they have a very important role in detecting cancer as a threat, initiating anti-tumor immune responses, and regulating the duration and magnitude of that immune response in the tumor.

Q: What are some examples of novel subsets and how do they relate to tumor growth?

Malay Haldar, MBBS, PhD: Mononuclear phagocytes really are three main cell types. You have monocytes, macrophages, and dendritic cells. However, that's a very simple view of it. Each of these cell types, each of these cell monocytes, macrophages, or dendritic cells (DCs) can actually take on further functionally specialized subtypes.

For example, we can think of dendritic cells. They come in many different flavors, and some examples would be conventional dendritic cell type 1, conventional dendritic cell type 2, or plasmacytoid dendritic cells. They have different phenotypes (you can distinguish them), and they have different functions (And I won't go into the details of the functional details here for the sake of time). Macrophages are actually even more diverse than dendritic cells. And the majority of what we know about these subsets of macrophages and dendritic cells come from studies in normal tissue in the body. One thing we realized is that, if you look in a particular organ or a tissue, the subtypes of macrophages or dendritic cells that exists there would often depend on the type of tissue itself.

For example, if you look at macrophages in the liver, they actually have very different function than those than those that you see in the lungs or spleen. As an extension of this overall observation, we have started realizing that macrophage, and even dendritic cell, composition in the tumor also depends on the type of tumor, much like what I just said about normal tissue. In other words, you'll see that macrophage subtypes are the subsets of macrophages that are there in breast cancer may be different from those in sarcoma, so brain tumor.

And what's important is that some macrophage subtypes can help tumor growth, while other subtypes actually can suppress tumor growth. It's not like all macrophages have the same function. They have subset specific functionality. And it's also important to note that the mechanism by which a certain subset of macrophage either promote or suppresses tumor growth is also different between different subtypes. I know it probably sounds confusing.

As an example, 1 macrophage subset might help tumors by suppressing the anti-tumor T cell response, while another pro-tumor macrophage subset might help tumors by helping it spread or metastasize (or help the tumor grow new blood vessels). Similarly, you know, macrophages can inhibit tumors, but that mechanism can also vary between subtypes. There are some macrophages that can suppress tumors by helping anti-tumor immune responses to T cells and other immune cells. And then there are some macrophages that can directly kill tumor cells without requiring help from these other immune cells.

So, for all these reasons, it's important for us to understand what type of macrophage and dendritic cells exist in a particular type of tumor. That way we can then start thinking about what's the best way to therapeutically target the cells so that overall, we increase more antitumor macrophages, dendritic cells, and at the same time reduce subsets that are helping the tumors.

Q: How does the immune system respond to different subsets of macrophages?

Malay Haldar, MBBS, PhD: One key thing about macrophages- they're very plastic in terms of what they can do. In other words, you can probably see a macrophage in the tumor that is helping the tumor by creating immunosuppression and other things that are said. But at the same time, that macrophage can still change its mind and end up helping anti-tumor immune responses if you target certain pathways. In other words, in macrophages, functional state, or function, can be changed in a therapeutic manner. But normally the macrophages that help the tumor and the macrophages that suppress the tumor are in 2 different functional states- but they're not set in stone. You can change the functionality by targeting certain pathways.

There are many subtypes of macrophages. Some that can help tumors grow whereas others are suppressive. In terms of what you brought up, like "how does the immune system interact with these macrophages?", that depends on the subtype of macrophages. For example, there is a type of macrophage known as pro-inflammatory macrophage, or also known as the M1 type macrophage which that helps immune responses against cancer by creating really an inflammatory environment. And within this, T cells and other immune cells are more effective in killing the tumor. So, they're creating an ambience that is more anti-tumor.

On the other hand, there are other types of macrophages, some of which are known as M2 type macrophages, or anti-macrophages, that actually suppresses immune responses by creating an environment where other immune cells find it difficult to kill the tumor. And in some cases, those macrophages actually promote tissue repair and wound healing. It's a kind of phenotype that you see after injury, where the body's trying to heal itself. And so that mechanism, which is the wound healing phenotype, actually is anti-inflammatory. And in that environment, the other immune cells have a hard time fighting cancer.

So, the interaction between macrophages and the overall immune system is different depending on what type of macrophage we're talking about- which is why, again to reiterate the point, we really need to understand the cells better in the tumor microenvironment. And as you can imagine, there is a lot of ongoing interest in coming up with therapeutic strategies- where we can really change the functionality of macrophage.

In other words, increase M1 macrophage, decrease M2 macrophage, and combine this therapeutic approach with things that already work like checkpoint blockade, CAR T-cells, other forms of engineered T cells, or even chemotherapies and radiation therapy. There's a lot of interest in targeting unique subsets, as long as we understand the subsets and what is it that we want to target, and then take it further by combining it with things that we already know work.

Q: What is the direction of future studies and research on novel subsets?

As a field, it is quite exciting times for many reasons. One of them is new single-cell technologies that allow us to deeply characterize individual cells and have recently become available. And scientists across the world have started applying these technologies to really understand (deeply and at an individual cell level) the composition of tumors and the validity of these technologies is really revolutionizing how we study cancer. At the same time is providing important new insights into the immune composition of the cells.

For us, people like us who study the innate immune system, we have found really interesting novel insights into macrophage and DC composition within tumors. I really think that these types of studies will finally unravel the complexities around macrophages, dendritic cell, monocytes, and other myeloid cell diversity. And this will finally allow us to target these cells rationally, rather than "let's just kill all macrophages because they're all bad." That won't work. Instead of that, once you understand the crew diversity, and who's doing what, we can selectively target these cells. That would probably allow us to expand the reach of immunotherapy to tumors that currently don't respond. That's the general state of the field in our own lab.

My team is very interested in discovering new subsets of these cells in tumors, and using technologies that I just mentioned, we are interested in understanding the diversity of the cells in normal tissues, as well as tumors, and understanding how these different subsets develop and function, with the goal of targeting them for treatment purposes.

Malay Haldar, MBBS, PhD: One of the things that we realized recently is that tumor cells themselves have an important role in in the development of these different subsets of macrophages and dendritic cells. So we are really interested in identifying the molecular pathways by which tumor cells are able to direct the development of these different subsets.

And another area of interest in our group is to study how these different subsets respond to therapy. And by therapy, I mean either chemoradiation or emerging immunotherapy- we have found that the subsets and their functionality changes can alter quite dramatically, in some cases under therapeutic treatment. If you understood how they're changing, maybe there is an opportunity to target those subsets, along with chemotherapy and radiation therapy, to get a synergistic effect.

Q: Closing thoughts?

Malay Haldar, MBBS, PhD: Generally speaking, this is a very exciting time to study cancer and try and cheat this disease that has defeated us for a long time. Finally, we have a treatment modality that is curative. In many cases, there are examples of immunotherapy where the patients have been in long-term remission and actually have been cured. So these are truly exciting times.

And the other reason- as an immunologist, I'm excited that understanding cancer immunology also opens windows. It also enhances your understanding of the basic immune responses, and how the immune system functions in other settings. Cancer is just 1 setting. The immune system was not just put in place to fight cancer- it was actually put in place mostly to fight pathogens and other pathologies. I'm very excited from both the point of view of basic immunology and what we can learn from this expanding area of research in cancer immunotherapy.

As far as CICON goes, I'll cover some of my work (although it is very difficult to cover all of what you're doing in 25 or 30 minutes) but I am planning to talk about unique subsets and go into details of how we discovered them, what we think they're doing, and how might that information use for devising new ways of treating cancer.