Reducing Myeloid-Derived Suppressor Cells in Hematological Malignancies

Sara McKee, Ph.D., Postdoctoral Fellow, University of Queensland
Sara McKee

Dr. McKee obtained her PhD at the University of Otago, New Zealand. She is currently a post-doctoral research fellow at Dr. Stephen Mattarollo’s lab at the University of Queensland Diamantina Institute. Dr. Mattarollo’s lab is interested on developing combination immunotherapies for hematologic malignancies, and Dr. McKee’s research is focused on antibody-based immunotherapy for B cell lymphoma.


Topics:

  • Monoclonal antibody therapy for cancer
  • Myeloid-derived suppressor cells

The Scientist: Sara McKee

1. What led you to your current role in Stephen Mattarollo’s lab?

I completed a BSc in Microbiology and Immunology at the University of Otago, New Zealand. My honours project was on the effect of environmental mycobacteria on BCG-specific T cells, which gave me my first insight into the wonderful world of immunology research. For my PhD I moved into the cancer immunotherapy field and developed a virus-like particle based therapy for melanoma. My first post-doctoral position was at the University of Queensland Diamantina Institute, where I worked on tissue-resident lymphocytes in pre-cancerous skin lesions. I then moved to Stephen Mattarollo’s lab to work on lymphoma.

2. What do you enjoy most about research?

I enjoy that everyday is different and that I am constantly learning. Nothing stays the same in science! Your ideas are always being challenged and you have to have a flexible mind to be open to new concepts.

3. Do you have any advice for students pursuing graduate studies?

Find a project in a field that excites you, long days in the lab are much easier when you are interested. Also, resilience! You need it by the bucket load in this field. If something is obvious and easy, it’s probably already been done. The most important and interesting experiments are often the hardest to do. They might fail the first time but stick with it and the satisfaction of finally getting an answer is worth the struggle.


The Science: Antibody Therapy for Cancer

1. Tell us about your research.

I am investigating the relationship between the myeloid compartment and lymphoma. Myeloid-derived suppressor cells are well defined in solid tumors, but less so in hematological malignancies. In a pre-clinical mouse model of B cell lymphoma I have observed marked expansion of immunosuppressive monocytes. These cells are proving to be the bad guys, so now I am seeking to understand how we can reduce their immunosuppressive ‘burden’, and give T cells their best shot at responding to monoclonal antibody therapies and kill lymphoma cells.

2. What is the significance of your research?

If we know what cells are working against T cell-mediated killing of lymphomas, we can screen for these cells at diagnosis. Knowing the immunological landscape of a patient is a very powerful tool for deciding treatment options. Pre-conditioning to reduce the immunosuppressive burden in patients could significantly improve response rates.

3. Where do you think the monoclonal antibodies therapy field is heading?

Combining monoclonal antibodies with other treatments that can enhance immunity such as small molecule inhibitors, chemotherapy or even other monoclonal antibodies will be the next step. Hitting tumours from as many angles as possible gives us the best shot at keeping them down.

4. What do you think is the most important advancement in the field in the past 5 years?

The field really is so young! The first reports from clinical trials with the use of anti-CTLA4 and anti-PD1 antibodies were published in the mid-late 2000s. There has been an absolute explosion since then with waves of clinical trials where we are seeing incredible responses to monoclonal antibody therapies. This year is the first time I have heard the word ‘cure’ used so freely at conferences.

5. What is the most challenging aspect of monoclonal antibody therapy research?

The biggest challenge at the moment is that we don’t know why some people respond and some people do not respond to these therapies. What we know is that the individuals that do respond tend to undergo incredible recoveries from their disease. If we could predict who the responders are, then appropriate application of mAb could decrease morbidity for these patients and reduce cost to the healthcare system.


EasySep™: Immune Cell Isolation

1. What do you use EasySep™ for?

I use the EasySep™ CD19 positive selection kit to remove my lymphoma cells from samples prior to FACS, and also the EasySep™ monocyte isolation kit to enrich for monocytes prior to FACS.

2. How has EasySep™ enabled your research?

EasySep™ allows me to pre-enrich my samples for FACS much faster and with less handling. Monocytes are so plastic and sensitive to external factors, and speed is essential when working with these cells. EasySep™ is the fastest separation kit out there.

3. Have you used a column-based cell isolation? What made you switch to EasySep™?

I prefer EasySep™ because all the preparation can be done in the FACS tube so there is much less handling of the cells compared with column-based separation kits. Not having to buy the expensive columns is also a bonus.

STEMCELL's Scientific Summaries

On monoclonal antibody therapy for cancer

Antibody-based therapy has proven to be one of the most successful strategies for cancer treatment. Monoclonal antibodies can either be directed towards malignant cells to promote their inhibition and antibody-dependent cell-mediated cytotoxicity, or directed towards immunosuppressive molecules that prevent effective immune responses toward tumor cells, including PD-1, CTLA-4 and CD471. CD47 is a protein expressed in various tumor cells that inhibits phagocytosis, and antibody-based therapies that block CD47 have proven efficacious in mouse models of cancer2. Several studies have also suggested the use of antibodies to agonistically activate the co-stimulatory receptor 4-1BB, which potentiates the anti-tumor activities of cytotoxic T cells and various other immune cell types3,4. Monoclonal antibody therapy to block CD47 and stimulate 4-1BB are both currently being evaluated in clinical trials. As Dr. McKee discussed above, understanding why some patients respond to antibody therapies and some do not, will be key in designing effective personalized cancer therapies.

More on cancer immunology

On myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) had initially been and may still be a controversial cell to immunologists. MDSCs are loosely defined as immature or non-terminally differentiated myeloid cells5. A major controversy is the lack of clear distinction between polymorphonuclear MDSCs and neutrophils, and between mononuclear MDSCs and monocytes6. Regardless, MDSCs have the capability to suppress immune cells using various mechanisms, including the secretion of immunosuppressive cytokines (ex. IL-10) and induction of regulatory T cells5. MDSCs accumulate in tumor microenvironments, where they blunt anti-tumor immunity and promote tumor growth and metastasis. Researchers are currently developing therapies to target MDSCs in cancer patients either by blocking their accumulation and function or promoting their differentiation into mature myeloid cells without immunosuppressive function7. Combining these therapies with those that directly promote tumor killing, including CAR T cell therapy, may be a winning strategy to eliminating tumor cells.

References

  1. Scott AM et al. (2012) Monoclonal antibodies in cancer therapy. Cancer Immun 12: 14.
  2. Liu X et al. (2015) CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 21(10): 1209-1215.
  3. Bartkowiak T and Curran MA. (2015) 4-1BB agonists: multi-potent potentiators of tumor immunity. Front Oncol 5: 117.
  4. Chester C et al. (2016) 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 65:10): 1243-8.
  5. Marvel D and Gabrilovich DI. (2015) Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 125(9): 3356-64.
  6. Bronte V et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7: 12150.
  7. Draghiciu O et al. (2015) Myeloid derived suppressor cells-an overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology 4(1): e954829.