An immunology revolution

Dr Santiago Zelenay is using his background in fundamental immunology to understand how the immune system can be used to design better therapies for cancer patients. As a recipient of the Cancer Research UK (CRUK) Future Leaders in Cancer Research Prize, Lead of the Cancer Immunology Branch of the Lydia Becker of Immunology and Inflammation and now the Lead of the Immunology Theme within the CRUK Lung Cancer Centre of Excellence, he shares details of his work and what inspired him to join the cancer community.

Over the years, I’ve become increasingly interested in the idea that the immune system not only constitutes a defence mechanism against infectious microorganisms, such as bacteria and viruses, but that it can also be a powerful barrier to cancer.

The notion that you could treat cancer patients with therapies that harness the power of the immune system has been around for a long time, but it was only over the last ten years that undeniable evidence showed these therapies can promote profound patient benefits across many different tumour types. In many cancer types, immunotherapy has replaced mainstream cancer treatments, like chemotherapy, as the standard of care.

Immunotherapies, especially those based on the use of so-called immune checkpoint inhibitors, have really transformed the clinical care of patients with cancer. There has been a revolution in this respect and also in thinking. All this clinical evidence has eradicated the scepticism around the concept that the immune system could block cancer development and progression.

As someone with a background in basic immunology, I was drawn to the idea of working on something with obvious clinical implications that could directly benefit patients. I wanted to apply my knowledge in fundamental immunology to cancer biology at a time of renaissance in the cancer immunology field.

This contributed to my decision to move to Manchester and join the CRUK Manchester Institute—an ideal place to continue basic research in cancer while focusing on translational aspects, facilitated by its connection with The Christie hospital, close interaction with oncologists and clinicians, and access to patient samples.

In recognition of the impact of my foundational research, together with co-authors, I was awarded in 2019 with the prestigious BIAL Award in Biomedicine for our groundbreaking work, which underpins many of the key research questions my group investigates today.

Dr Santiago Zelenay

Santiago Zelenay is the lead for the Cancer Inflammation and Immunity Group at the Cancer Research UK Manchester Institute and Cancer Immunology lead at the Lydia Becker Institute at The University of Manchester.

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Investigating inflammation

My research group focuses on understanding the principles and rules that regulate the balance between tumour-promoting and tumour-inhibitory inflammation. Inflammation can have a dual role in cancer, promoting or restricting its growth.

This also happens following treatment, but little is understood about what determines whether the outcome is good or bad. We study how this happens and whether we can therapeutically change the way our immune system responds to cancer to make treatments more effective.

We ask fundamental questions: what kicks off the immune response against cancer in the first place, and what prevents this from happening? What is the key to a strong and durable response? How can we predict who will respond before treatment starts? How can we therapeutically make an unresponsive tumour respond to immunotherapy?

Through the study of the inflammatory response within tumours, we aim to design new combinations to enhance the efficacy of treatments. Our ultimate goal is to contribute to more efficient therapies for cancer patients.

Research discovery

In asking these basic questions, we found that anti-inflammatory drugs, such as aspirin, can improve the efficacy of immunotherapy in preclinical models of cancer. Based on these findings, we are contributing to multiple clinical trials designed to test promising combinations.

One such trial, LION (Lifting Immune CheckpOints with NSAIDs), has recently opened and is testing whether adding celecoxib, an anti-inflammatory drug commonly used for the management of inflammatory diseases such as rheumatoid arthritis, enhances the efficacy of standard-of-care immunotherapy in patients with advanced lung, breast, and kidney cancers.

Made possible by funding from The Christie Charity and The Jon Moulton Charity Trust, LION is led by Dr Anne Armstrong, consultant medical oncologist in breast cancer in collaboration with lung cancer consultant Dr Colin Lindsay, and renal cancer consultant Dr Tom Waddell, all from The Christie NHS Foundation Trust,

These trials reflect a broader premise: anti-inflammatory drugs like aspirin, rather than indiscriminately inhibiting tumour inflammation, can reshape its 'flavour' into a type that promotes higher response rates.

The Manchester advantage

Manchester is unique because of its collaborative spirit. We may have diverse expertise, but we all work together toward a single goal: improving patient outcomes. Our seamless interactions with oncologists and clinicians set us apart.

At The University of Manchester, we also benefit from a vibrant immunology community. Collaborations with colleagues at the Lydia Becker Institute of Immunology and Inflammation and at the CRUK National Biomarker Centre have been transformative. Thanks to this collaborative nature and 'Team Science' spirit, I've built multiple new partnerships and expanded the scope of my research to bridge basic science and clinical application.

This ecosystem allows us to redefine ourselves as researchers. While I began as a pure fundamental immunologist, my work now spans from foundational research to clinical trials, leveraging Manchester's integrated research environment.