Targeting immune cells could improve colorectal cancer treatments

Researchers at the Medical University of Vienna have described a mechanism in metastatic colorectal cancer that has received little attention to date: a key target of existing therapies, the so-called epidermal growth factor receptor (EGFR), is likely to affect more than just the cancer cells themselves. The study shows that EGFR also influences certain immune cells in the tumor microenvironment - and thereby helps determine how effectively the body's own defenses can combat the tumor. The findings have recently been published in the journal Cell Death & Differentiation.

Metastatic colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Targeted therapies that block the epidermal growth factor receptor (EGFR) are already available for certain patients. EGFR is a type of receptor on the cell surface through which cells can receive growth signals. This signalling pathway plays an important role in several types of cancer.

EGFR-inhibiting antibodies are already used in colorectal cancer, particularly in patients without certain KRAS mutations. However, not all patients respond sufficiently to this treatment. Furthermore, tumors can become resistant during the course of therapy. The cause of this is only partially understood so far.

Immune cells as a key component of the therapeutic effect

The research team led by Maria Sibilia from the Center for Cancer Research at MedUni Vienna and the Comprehensive Cancer Centre at MedUni Vienna and University Hospital Vienna has now investigated the role EGFR plays in certain immune cells. The focus was on so-called myeloid cells. These include, among others, macrophages, which normally eliminate pathogens or damaged tissue in the body. However, in the vicinity of a tumor, they can also play the opposite role and promote tumor growth.

Studies in preclinical models, supplemented by modern single-cell and proteome analyses as well as data from patient cohorts, revealed a clear pattern: when EGFR was specifically silenced in these myeloid cells, tumors grew significantly more slowly. In contrast, when EGFR was removed only from the colorectal tumor cells themselves, no comparable therapeutic effect was observed.

This suggests that EGFR-targeted therapies do not work solely by directly influencing cancer cells. A significant part of the effect could be mediated by altering the immune system within the tumor microenvironment.

Tumor microenvironment becomes more favorable for immune cells

The targeted silencing of EGFR in myeloid cells led to reduced production of factors that normally inhibit T cells. T cells are key defence cells of the immune system and are capable of recognizing and attacking cancer cells. If their activity is suppressed within the tumor, the tumor can grow more easily.

Our results show that EGFR in myeloid cells is a key regulator of the tumor-promoting immune landscape. 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 tumor cells, the results show that EGFR in myeloid cells creates a tumor-promoting microenvironment."

Maria Sibilia, study lead 

Fewer tumor-promoting macrophages

The effect was particularly pronounced in certain subgroups of macrophages. These immune cells can create a protective environment for cancer cells within the tumor and are associated with a poorer prognosis. In the study, these tumor-promoting macrophages declined when EGFR was silenced in myeloid cells.

At the same time, key inflammatory signals within the tumor changed. This also altered communication between different immune cells. Overall, the tumor microenvironment became less suppressive of the body's own immune defense.

THBS1 as a potential indicator of disease progression

The research team also identified the protein thrombospondin-1, or THBS1 for short, as an important messenger molecule. THBS1 is released by myeloid cells and can interact with T cells. The analyses showed that EGFR signals influence the formation of THBS1.

Data from colorectal cancer patients also showed that high levels of EGFR and THBS1 were associated with a poorer disease prognosis. THBS1 could therefore be further investigated in the future as a potential biomarker - that is, as a measurable indicator of how the disease is progressing or the nature of the tumor microenvironment.

New approach for future therapies

The study suggests that future therapies for metastatic colorectal cancer should not only target cancer cells directly. Certain immune cells in the tumor microenvironment could also be an important target.

"Our study shows that the targeted modulation of EGFR signaling in certain immune cells could represent a promising new treatment strategy for metastatic colorectal cancer," said Maria Sibilia.