New research from the Olivia Newton-John Cancer Research Institute (ONJCRI), led by PhD candidate Andrew Li, has shed light on an immune response that could open the door to more effective colorectal (bowel) cancer treatments.
Every cell in the body displays a molecule on its surface called MHC class I (MHC-I). When a cell becomes cancerous, MHC-I reflects this, and specialised immune cells called CD8+ T cells recognise the abnormal MHC-I signal and destroy the cell.
Some cancers gradually reduce or completely switch off their MHC-I molecules to help them evade the immune system. The tumour becomes “invisible” to the CD8+ T cells. However, it is not well understood how other types of immune cells respond in this context.
Gamma-delta (γδ) T cells are a lesser-known player of the immune system. Unlike conventional T cells, they do not rely on MHC-I to identify their targets. This makes them suited to detect and attack the tumours that have learned to hide from conventional immune surveillance.
This study investigated how γδ T cells behave in human colorectal cancers that have lost MHC-I.
Andrew and the team analysed 150 colorectal cancer patient samples spanning all four disease stages, using a sophisticated imaging technique called multispectral immunohistochemistry. This approach uses multiple fluorescent markers simultaneously to identify and count different cell types within the tumour architecture.
The first major finding was that across all disease stages, roughly 30% of colorectal tumours had lost MHC-I expression. For a disease as common as colorectal cancer, 30% represents many patients, and a large group for whom therapies that depend on MHC-I-mediated immune recognition may be working at a disadvantage.
The second finding was striking. In stage III tumours, MHC-I loss was associated with a significant increase in activated γδ T cells in the tumour environment. This suggests that these cells may be engaging with the tumour environment in a way that conventional T cells are not.
“By providing the first detailed look at how γδ T cells behave inside human colorectal tumours that have lost MHC-I expression, this work identifies a crucial backup defence system that could be harnessed to design smarter immunotherapies for patients who don’t respond to current treatments,” Andrew said.
For the approximately one in three patients whose tumours have silenced their MHC-I machinery, current immunotherapy approaches offer limited benefit. This study provides some of the clearest evidence yet that the immune system has a backup plan, and that γδ T cells may be at the centre of it.
This new data provides a compelling rationale for looking more closely at γδ T cells in the development of new, more effective and targeted cancer treatments.
More than 5,300 Australians lose their lives to colorectal cancer every year.¹
The work, published in Clinical & Translational Immunology, was supported by the Austin Medical Research Foundation, the Victorian Cancer Agency, a Postgraduate Student Grant from Tour de Cure Australia, and was made possible by tissue samples collected at Austin Health.
¹ https://www.bowelcanceraustralia.org/bowel-cancer/bowel-cancer-facts/