Weight loss condition provides insight into failure of cancer immunotherapies

Cancer immunotherapies involve activating a patient’s immune cells to recognise and destroy cancer cells. They have shown great promise in some cancers, but so far have only been effective in a minority of patients with cancer. The reasons behind these limitations are not clear.

Now, researchers at the Cancer Research UK Cambridge Institute at the University of Cambridge have found evidence that the mechanism behind a weight loss condition that affects patients with cancer could also be making immunotherapies ineffective. The condition, known as cancer cachexia, causes loss of appetite, weight loss and wasting in most patients with cancer towards the end of their lives. However, cachexia often starts to affect patients with certain cancers, such as pancreatic cancer, much earlier in the course of their disease.

In research published today in the journal Cell Metabolism, the scientists have shown in mice that even at the early stages of cancer development, before cachexia is apparent, a protein released by the cancer changes the way the body, in particular the liver, processes its own nutrient stores.

“The consequences of this alteration are revealed at times of reduced food intake, where this messaging protein renders the liver incapable of generating sources of energy that the rest of the body can use,” explains Thomas Flint, an MB/PhD student from the University of Cambridge School of Clinical Medicine and co-first author of the study. “This inability to generate energy sources triggers a second messaging process in the body – a hormonal response – that suppresses the immune cell reaction to cancers, and causes failure of anti-cancer immunotherapies.”

“Cancer immunotherapy might completely transform how we treat cancer in the future – if we can make it work for more patients,” says Dr Tobias Janowitz, Medical Oncologist and Academic Lecturer at the Department of Oncology at the University of Cambridge and co-first author. “Our work suggests that a combination therapy that either involves correction of the metabolic abnormalities, or that targets the resulting hormonal response, may protect the patient’s immune system and help make effective immunotherapy a reality for more patients.”

The next step for the team is to see how this discovery might be translated for the benefit of patients with cancer.

“If the phenomenon that we’ve described helps us to divide patients into likely responders and non-responders to immunotherapy, then we can use those findings in early stage clinical trials to get better information on the use of new immunotherapies,” says Professor Duncan Jodrell, director of the Early Phase Trials Team at the Cambridge Cancer Centre and co-author of the study.

“We need to do much more work in order to transform these results into safe, effective therapies for patients, however,” adds Professor Douglas Fearon, Emeritus Sheila Joan Smith Professor of Immunology at the University of Cambridge and the senior author, who is now also working at Cold Spring Harbor Laboratory and Weill Cornell Medical College. “Even so, the results raise the distinct possibility of future cancer therapies that are designed to target how the patient’s own body responds to cancer, with simultaneous benefit for reducing weight loss and boosting immunotherapy.”

The research was largely funded by Cancer Research UK, the Lustgarten Foundation, the Wellcome Trust and the Rosetrees Trust.

Nell Barrie, senior science information manager at Cancer Research UK, said: "Understanding the complicated biological processes at the heart of cancer is crucial for tackling the disease - and this study sheds light on why many cancer patients suffer from both loss of weight and appetite, and how their immune systems are affected by this process. Although this research is in its early stages, it has the potential to help make a difference on both fronts - helping treat weight loss and also improving treatments that boost the power of the immune system to destroy cancer cells."

Reference
Flint, TR et al. Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. Cell Metabolism; 8 Nov 2016; DOI: 10.1016/j.cmet.2016.10.010