Targeting 'Zombie’ cells gives hope in treating drug resistant lung cancer

 1 June 2023   Public Science

By Sofia Velazquez Pimentel

Breakthrough discovery in new publication could have significant implications for the treatment of certain types of lung cancer. Researchers at MRC LMS have participated in a collaborative effort lead by UCL, and Cambridge University found that senescent ‘zombie’ macrophages, a type of immune cell, are a major player in the progression of lung cancer. Remarkably, killing these ‘zombie’ macrophages reduce tumour size and increase life expectancy in mice, presenting a potential new avenue for lung cancer treatment.

Cellular senescence is a phenomenon whereby a cell is ‘stuck’ in the cell cycle, they are often nicknamed ‘zombie cells’ as they refuse to die. If senescent cells accumulate, the cells release toxic signals triggering cancer and ageing. Understanding senescence’s role in cancer could help us combat even the most treatment-resistant cancers, such as those with the KRAS mutation.

Identifying which cell types become senescent has always been a barrier to understanding their role in cancer. Researchers at UCL have pioneered a new innovative mouse model named P16-FDR which will empowers scientists to accurately identify, isolate, trace, and selectively kill senescent cells within living organisms. The implications of this pioneering development allowed the researchers to identify and visualise cell populations involved in tumour development and age-related abnormalities in the lung.

Using state-of-the-art Single-Cell RNA-Sequencing (scRNA-Seq) technology with the MRC LMS Genomics Facility, the MRC LMS Senescence Group and the University of Cambridge deciphered specifically which cell types were undergoing senescence in KRAS mutant lung cancer and during ageing.

To their surprise, the researchers discovered that senescence was not primarily attributed to the lung’s tissue cells themselves but rather to the immune system’s macrophages. The team discovered that macrophages that had become senescent were interfering with the immune system’s normal ability to eliminate tumours, thereby posing a major obstacle in the context of lung cancer. Amazingly, these abnormal senescent macrophages were also detected in ageing tissues of mice. This indicates they may also be major players in both lung cancer and age-related tissue defects.

Dr Virinder Reen, researcher in the MRC LMS Senescence Research group visualizing data showing the surprising role of macrophages in lung cancer.

The researchers found that the mouse model allowed them to detect senescent macrophages at the initial stages of tumour development.  Using drugs that kill senescent macrophages the team were able to revive the anti-tumour immune response, reducing the size of lung tumours and increasing mouse lifespan.

In mice, the removal of senescent macrophages resulted in a reduction in tumour lesions (shown in green).

Importantly, the researchers also found that senescent macrophages were also present in human lung tumours. These findings show targeting senescent macrophages could be an effective new way to combat even the most treatment resistant lung cancers.

Dr Virinder Reen, researcher in the MRC LMS senescence Research group stated ‘I was very privileged to be able to contribute to such a collaborative research effort during my PhD. Using novel genetic and computational tools, we were able to decipher the role that specific senescent cells play in the initial stages of a tumour and how these can be prevented by targeting senescent macrophages. Now, we are all very excited to discover the impact our findings may have in a clinical setting, and perhaps uncovering whether eliminating senescent cells could have a potential therapeutic avenue for other KRAS-mutant tumours!’

Dr Scott Haston from the UCL GOS Institute of Child Health and lead researcher of the new publication said, ‘This breakthrough not only deepens our understanding of the disease but also paves the way for developing preventative therapies that can specifically target and inhibit these harmful effects, reducing the risk of lung cancer and potentially offering hope for a future where we can effectively prevent this devastating disease.’

This research was published in Cancer Cell and done by the MRC LMS Senescence Group in collaboration with the University College London Institute of Child Health (UCL ICH) and the University of Cambridge, supported by the MRC LMS Genomics Facility. Reference, Haston et al., 2023 Cancer Cell 41, 1-19

The study was core funded by the Medical Research Council, Worldwide Cancer Research and Cancer Research UK.

A study from the Mayo Clinic (Prieto et al., 2023) also came to a similar conclusion and was also published in Cancer Cell.