MedUni Vienna: Colorectal Cancer Research Is Placing Greater Emphasis on Immune Cells
Researchers at MedUni Vienna have identified a previously underestimated mechanism in metastatic colorectal cancer showing that the epidermal growth factor receptor (EGFR), a key target of existing therapies, also regulates immune cells within the tumour microenvironment. The findings suggest that future therapies could become more effective by targeting not only cancer cells but also specific immune cells that influence tumour growth.
The study, led by Maria Sibilia from the Center for Cancer Research and the Comprehensive Cancer Center at MedUni Vienna and University Hospital Vienna, has been published in Cell Death & Differentiation.
Metastatic colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Targeted therapies that inhibit the epidermal growth factor receptor (EGFR) are already used in selected patients, particularly those without certain KRAS mutations. However, many patients respond only partially to treatment or eventually develop resistance, and the underlying mechanisms have remained incompletely understood.
Immune Cells Play a Central Role
The researchers investigated the role of EGFR in myeloid cells, a group of immune cells that includes macrophages. While macrophages normally protect the body by removing pathogens and damaged tissue, they can also promote tumour growth within the tumour microenvironment.
Using preclinical models together with single-cell sequencing, proteome analyses and patient data, the team demonstrated that selective inhibition of EGFR in myeloid cells significantly slowed tumour growth. In contrast, removing EGFR only from colorectal cancer cells did not produce a comparable therapeutic effect.
The findings indicate that anti-EGFR therapies may exert a substantial part of their therapeutic activity through modulation of the immune system rather than acting exclusively on tumour cells.
More Favourable Tumour Microenvironment
Silencing EGFR in myeloid cells reduced the production of molecules that suppress T-cell activity. As T cells are responsible for recognising and destroying cancer cells, reducing this immune suppression allowed the body's natural anti-tumour response to become more active.
"Our results show that EGFR in myeloid cells is a key regulator of the tumour-promoting immune landscape," explained study leader Maria Sibilia. "In this study, we have discovered an unexpected mechanism underlying the therapeutic effects of anti-EGFR treatment in colorectal cancer. Rather than acting primarily via tumour cells, the results show that EGFR in myeloid cells creates a tumour-promoting microenvironment."
Reduction of Tumour-Promoting Macrophages
The most pronounced effects were observed in specific macrophage subpopulations that are associated with poor clinical outcomes. Following EGFR inhibition in myeloid cells, these tumour-promoting macrophages were significantly reduced.
At the same time, inflammatory signalling within the tumour changed, altering communication between immune cells and creating a tumour microenvironment that was less capable of suppressing the body's immune response.
THBS1 Identified as a Potential Biomarker
The researchers also identified thrombospondin-1 (THBS1) as an important signalling protein released by myeloid cells. EGFR activity was shown to regulate THBS1 production, and analyses of colorectal cancer patient samples revealed that elevated levels of both EGFR and THBS1 were associated with poorer clinical outcomes.
These findings suggest that THBS1 could serve as a future biomarker to assess disease progression and characterize the tumour microenvironment.
New Opportunities for Targeted Therapy
The study highlights the importance of considering immune cells alongside cancer cells when developing future treatments for metastatic colorectal cancer.
"Our study shows that the targeted modulation of EGFR signalling in certain immune cells could represent a promising new treatment strategy for metastatic colorectal cancer," said Maria Sibilia.