Written by:
Chief Scientist, Cancer Immunology,
AstraZeneca
Executive Director, Head of tumour microenvironment, AstraZeneca
In our relentless quest for innovation, we strive to gain a deeper understanding of disease biology with the aim of identifying new ways to target and treat cancer. As we look towards the future of immuno-oncology (IO) therapies we are asking questions about the interactions of cancer cells with the immune system, and the role of the tumour microenvironment (TME) in cancer progression.
What is the tumour microenvironment?
Tumours develop in complex microenvironments that facilitate critical steps in cancer formation, invasion and spread.1 This has led researchers to conclude that the "tumour microenvironment is not just a silent bystander, but rather an active promoter of cancer progression" (Truffi et al., 2020), that can impact the success of a treatment.1 One aspect of our research focuses on the potential to manipulate the TME to encourage anti-tumour immune responses.2,3
Exploring the role of myeloid cells in the TME
Myeloid cells are an essential part of the body’s innate immune response,4 and play a major role in promoting the recognition and elimination of tumour cells while leaving healthy cells unharmed.5
In the TME, the accumulation of tumour-associated myeloid cells with immunosuppressive properties has been associated with poor patient outcomes and treatment resistance, making them promising therapeutic targets.6 However, further research is required to unlock their potential.
As we gain more insight into the role of different myeloid cell populations, it’s evident that understanding both the disease-stage and tissue-specific role of myeloid cells is critical to developing myeloid-targeted medicines. We recently published a comprehensive review of our learnings to date:6
Myeloid cells have the ability to adapt and respond differently across tissue compartments, making it challenging to define their role in cancer and target them therapeutically. Their plasticity reflects their native role, during which they regulate an ongoing immune response in an agile way and optimise the host defence by turning on, or suppressing, pro-inflammatory pathways.7
In cancer, this plasticity helps differentiate myeloid cells into myeloid-derived suppressor cells (MDSCs) as part of the pathological activation that takes place in the TME, enabling cancer cells to evade the immune system.7 In our recent publication we identify a new mechanism, lipid peroxidation, as a major driver behind this pathological activation.7
The impact of ferroptosis on myeloid-derived suppressor cells (MDSCs)
With this knowledge, it is clear that we need to target myeloid cells early on, before they differentiate into MDSCs and develop immune-suppressive properties.
Another promising new mechanism we are exploring is ferroptosis, a type of regulated cell death that occurs exclusively in the TME and is associated with lipid peroxidation. Our research revealed that ferroptosis renders myeloid cells more immunosuppressive in mice, and makes immune checkpoint inhibitors less effective.8
To our knowledge, this is the first time that the immune suppressive role of ferroptosis has been proposed in cancer.
Learn more about how ferroptosis impacts cancer in the below video:
Therapeutic targeting of peroxynitrite from myeloid cells
Some cancer immunotherapies depend on T cells targeting specific antigens on the surface of cancer cells. We recently showed that a potent oxidant, known as peroxynitrite (PNT), produced by myeloid cells in the TME, can alter these antigens and help cancer cells evade immunotherapies.9
We showed that therapeutic targeting of PNT can reduce tumour resistance to cytotoxic T cells in mice, creating new avenues for designing novel cancer treatments.9
Discover our thoughts on targeting PNT production to enhance future immunotherapies in the below video:
The future of myeloid cells in shaping anti-tumour responses
As we learn more about myeloid cells, it helps to expand our knowledge of ways to target cancer, for example by blocking myeloid cell migration into the TME and by limiting their interplay with NK cells involved in immunosurveillance. Through these efforts, we hope to inform new drug combinations in the clinic, and improve treatment responses in early disease.
Join us as we continue to explore the TME
We welcome committed, talented scientists to join us on what promises to be one of the most exciting, stimulating and rewarding journeys in 21st century medicine.
A leader in oncology with a global footprint, we are growing a differentiated pipeline to address a range of tumour types associated with significant unmet need. There are limitless opportunities to make your mark, take smart risks and pioneer new ideas. Diverse in experience and approach, our team shares a passion to follow the science and bring life-changing medicines to people across the globe.
We recruit scientists with relevant expertise to join us in our state-of-the-art research facilities in Cambridge, UK, and Gaithersburg, US.
