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Mining the Mysteries of Myeloid Cells with CRI Lloyd J. Old STAR Malay Haldar

28 de marzo de 2022

In war, precision matters. Hitting the right targets and eliminating them while minimizing harm to non-combatants is essential to achieving victory. With cancer, precision is just as important. Without it, treatments can have unintended and unwanted consequences including short- and long-term side effects. 

Fortunately, our immune system has evolved to operate with a high degree of sophistication that allows its various components to communicate and coordinate their attacks against tumors. The complexity and adaptability of the immune response makes it an ideal weapon to outpace and outfight cancer. 

Two crucial elements of our immune arsenal are lymphoid cells known as T and B cells, and myeloid cells. Both lymphoid and myeloid cells originate in bone marrow, but they have unique, separate, and complementary functions. T and B cells are the soldiers of the immune system, highly specialized and capable of eliminating harmful tumors. These fight-ready cells, however, need supervision and training from myeloid cells, the conductors of the immune system, in order to perform their functions optimally.

Dr. Malay HaldarCRI Lloyd J. Old STAR Malay Haldar, M.D., Ph.D., an assistant professor of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medicine, is studying the role myeloid cells play in cancer immunity, specifically how they communicate with T and B cells as well as cancer cells. By defining the factors that influence myeloid cell behavior, he hopes to discover ways to exploit them and unlock more of cancer immunotherapy’s power.

We spoke with Dr. Haldar recently to learn more about his research goals and how he hopes his work will impact the field of cancer immunology and immunotherapy.

VIDEO TRANSCRIPT

Arthur Brodsky, Ph.D.

Hi, I'm Dr. Arthur Brodsky, assistant director of scientific content at the Cancer Research Institute, and today I'm grateful to be joined by Dr. Malay Haldar, a CRI Lloyd J. Old STAR at the University of Pennsylvania. Welcome, Dr. Haldar!

Malay Haldar, Ph.D.

Thank you, it's great to be here.

Arthur Brodsky, Ph.D.

In cancer, T cells get much of the glory, perhaps because they can target tumor cells directly and eliminate them with precision. But the effectiveness of T cells depends on another group of immune cells that you're exploring called mononuclear phagocytes. These immune cells, which are also known as myeloid cells, or rather are in the group of myeloid cells, they come in diverse types with some that can promote immune activity and others that can suppress it. And if the latter dominate in the tumor microenvironment, cancers can evade and escape immune responses.

I was hoping you could share with us a little about what are the different types of these myeloid cells, and what do we know about the roles that they normally play as well as in cancer?

Malay Haldar, Ph.D.

As you mentioned before, myeloid cells and lymphoid cells (T and B cells) are different types of white blood cells that participate in immune responses. They come from different precursors in the bone marrow and have distinct functions. There are different types of myeloid cells, and the ones we focus on mostly in our lab are known as antigen presenting cells. In terms of when you're thinking of the roles of these different cell types in cancer, a good analogy is to think about the immune system as a well-organized military or army. Lymphocytes, much like your T cells and B cells, are the soldiers of the army. They are primary cells responsible for killing the tumors and therefore, as you pointed out, they have garnered a lot of attention for cancer immunotherapy.

However, they need instructions and training so that they can distinguish a cancer cell from normal cells in the body. This instruction is given by antigen presenting cells. You can think of these antigen presenting cells much like the generals in the military or the army. They collect information from different sources to distinguish a cancer threat from normal tissue in the body. Then they convey this information to the T cells, telling them exactly what to look for, how to look for these cancer cells, and what strategies they might use to neutralize these cells. Armed with this information, T cells go to tumors to eradicate them.

Perhaps with this analogy, it's somewhat easier to appreciate that for tumors to avoid immune responses, a good strategy would be to convince these antigen presenting myeloid cells that tumors are not a threat. The tumors can do this by various different ways. They can start recruiting more immunosuppressive macrophages, which are a type of myeloid cells that can shut down the function of anti-tumor T cells, or tumors can inhibit functions of another type of antigen presenting myeloid cells known as dendritic cells. Apart from these macrophages and dendritic cells, another type of myeloid cells that are important to us is known as monocytes. Monocytes can actually differentiate into macrophages or dendritic cells, and tumors often interfere with this differentiation process for their own benefit. Besides monocytes, macrophages and DCs (dendritic cells) that I just mentioned, there are also other types of myeloid cells like neutrophils, basophils, but they're relatively rare inside the tumors, and we know much less about their roles in cancer immunity.

Arthur Brodsky, Ph.D.

I just want to clear up something for our listeners. You mentioned antigen presenting cells and I want to clear up the antigens are those actual, the ones that tell the T cells what the what the threat looks like, in this case cancer. The antigen is just that marker, that is the specific molecule to actually go after for the T cells.

As a CRI STAR, you're exploring how tumors and these myeloid cells communicate.  What are some of the important outstanding questions regarding myeloid cells and their impact on cancer immunity? How might your work help us overcome some of the current limitations of cancer immunotherapy and improve care for patients?

Malay Haldar, Ph.D.

Despite all the recent successes and excitement with T cell-focused immunotherapy, there are several major hurdles in the field. One is, as I mentioned before, the body does not recognize tumors as a threat, and therefore does not generate enough anti-tumor T cells. The other bottleneck is even if you have generated anti-tumor T cells, either naturally or through treatments, they're often shut down in the tumor microenvironment by these suppressive myeloid cells.

What scientists have realized in recent years is that tumors are constantly trying to inhibit the so-called "good" myeloid cells, such as dendritic cells, while at the same time promoting "bad" myeloid cells, such as the suppressive macrophages. What we have also realized is that different tumors employ different strategies to achieve this through communication between cancer and myeloid cells.

My group is trying to understand the molecular language of this communication with the overall goal of using this information to alter myeloid cell behavior and the distribution in tumors for immunotherapy. One example of this type of work is a recent publication from our group, showing that some tumors produce large amounts of retinoic acid, which causes monocytes to generate more of the immunosuppressive macrophages I mentioned before. If we inhibit retinoic acid activity in these tumors, we can now generate fewer macrophages and more dendritic cells. The end result of this is that we generate stronger, more robust anti-tumor immune responses. We are currently building on this discovery by developing novel inhibitors of retinoic acid production and signaling with the goal of taking these to clinical trials in the near future. We have also recently discovered other pathways that are distinct from the network acid-based pathway I just mentioned. We are trying to understand how these other pathways also regulate antitumor immune responses to myeloid cells. The overarching goal always is to find therapeutic vulnerabilities that we can exploit for new treatment approaches.

Arthur Brodsky, Ph.D.

Interesting. Essentially, it sounds like you're trying to disrupt that bad feedback cycle that gives rise to the myeloid cells that shut down the T cells. Then, if you could disrupt that, then the T cells not only might they be able to do their job better naturally without extra help, but then presumably also the checkpoint immunotherapies and others that target the T cells, then they might work better too, correct?

Malay Haldar, Ph.D.

That's right, absolutely, yeah.

Arthur Brodsky, Ph.D.

As you're going about answering these challenges, or answering these questions, what are some of the biggest challenges as far as learning more about myeloid biology? Are there any technological challenges that you're addressing at the same time in order to answer these questions?

Malay Haldar, Ph.D.

Right, so the myeloid cell types that I just mentioned before come in various different functional types. Furthermore, different types of tumors would often contain different subtypes of these cells. A major challenge currently is to understand which tumors harbor what types of these cells and how might these be affecting the anti-tumor immune responses.

The other challenge that I also mentioned before is that we have very limited understanding of this crosstalk between cancer and myeloid cells, by which the tumors really convert some of these myeloid cells from a foe to an ally. In many cases, we know that intratumoral myeloid cells can end up helping the cancer grow and spread. To address some of these challenges, which is mostly related to diversity and heterogeneity of these cells, we are employing now cutting-edge single-cell technologies using both mouse models as well as human tumors.

Arthur Brodsky, Ph.D.

You mentioned the single cell technologies. I think this is especially important, given you've been talking about the kind of diversity and complexity of these myeloid cells. The current state of understanding, it's not quite clear necessarily what makes the progenitors that give rise to all the other subsets, what kind of causes it. Hopefully, you'll be able to make some progress there.

Zooming out a little bit, what do you hope to accomplish over the next five years as a CRI STAR, and how do you hope that your work will impact the field?

Malay Haldar, Ph.D.

The next five years we really hope to discover additional pathways, much like the retinoic acid pathway I just described before, that underlie this communication between cancer and myeloid cells. Another major hope is that we will be able to transition some of our basic discoveries into clinical trials. We're actually already engaged in one such study, where we are examining the safety and efficacy of our new compound. It's a first-in-class compound that we have jointly developed with NIH to target the retinoic acid pathway, specifically in liver cancer to begin with. Our hope is that we will be able to start a Phase 1 trial very soon, once we have completed these safety studies. Generally speaking, the overall hope is that our work will impact both the basic understanding of tumor immunity as well as the landscape of cancer therapy.

Arthur Brodsky, Ph.D.

That's great to hear. Obviously, the basic science is important, the discoveries are exciting, but at the end of the day it's all about helping people. I think in the public there's not a lot of understanding necessarily about how scientific grants work, and how different programs supply funding. I was hoping, could you explain why this CRI STAR funding is so important for your research? And specifically, what will this support enable you to pursue that you might not have been able to otherwise?

Malay Haldar, Ph.D.

A key component of this award is that it is really not tied to a very specific project. What happens normally in a funded project is that we end up discovering new and completely unanticipated things during the course of the study. It's very difficult to pursue these exciting, but new lines of investigation because, generally speaking, most fundings have a very narrow focus. If you wanted to do that, if you wanted to pursue these new lines of investigation, you will have to write a new grant, wait for it to be reviewed, get the funding and then start. In contrast, the CRI funding is very different, as it does not really restrict us to a very specific line of investigation. It's broadly encompassing tumor immunotherapy. This really allows us to be nimble and expedite and actually enable studies that will be otherwise very difficult to pursue. In summary, this award really enhances both the time and ease of working on that.

Arthur Brodsky, Ph.D.

You bring up a great point that science is not something where we necessarily know the destination. The journey is very mysterious. That's why we have to go into the unknown to answer those questions. Thank you very much Dr. Hadar, for taking the time to speak with me today, and great luck in your work. I can't wait to follow your progress!

Malay Haldar, Ph.D.

Thanks for the interview and thanks for your support! Really a pleasure.

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