Immunotherapies are designed to empower the body’s own immune cells to recognise and destroy cancer cells.

However, many patients respond poorly to these treatments. One major reason is that immune cells often fail to enter tumours in sufficient numbers.

A research team led by Hellmut Augustin of DKFZ and Heidelberg University therefore set out to investigate the role of tumour blood vessels in this process.

Blood vessels guide immune cells

The researchers focused on liver metastases, which commonly occur in advanced cancer and are often difficult to treat with immunotherapy.

Within the blood vessels of metastases, the team identified a specialised subgroup of endothelial cells, the cells lining the inside of blood vessels.

These cells produce lipoprotein lipase (LPL), a key enzyme involved in fat metabolism. The LPL-producing endothelial cells act like guides for activated T cells, the immune cells capable of specifically attacking cancer cells.

The more LPL-producing endothelial cells were present, the more T cells were able to enter the tumour and fight cancer cells.

Blood vessel cells display a “wanted poster” of the tumour

The researchers discovered that these LPL-rich endothelial cells can present tumour-derived components on their surface, a process known as antigen presentation.

This function is normally performed by specialised immune cells.

The team has now shown that LPL also enables this specific subgroup of endothelial cells within tumours to perform this task.

Endothelial cells display a molecular “wanted poster” of the tumour to passing T cells, alerting them to the presence of cancer cells.

As a result, T cells can more readily recognise where tumour tissue is located and migrate from the bloodstream into the tumour, where they can exert their cancer-fighting functions.

“Blood vessels are not merely passive pipelines supplying blood to tumours. They actively instruct the immune system and help T cells recognise and attack metastatic cancer cells,” says Xiaowen Zhang, first author of the study.

LPL improves tumour control

In several experimental mouse models of melanoma metastasis in the liver, the researchers found that increasing LPL levels in endothelial cells allowed more T cells to enter the metastases, leading to stronger tumour regression.

Conversely, when LPL was switched off, the immune response was significantly weaker. This discovery opens new perspectives for cancer immunotherapy.

In particular, for so-called “immunologically cold” tumours, which espond poorly to immunotherapy, targeted activation of this mechanism may help in the future to recruit more immune cells into tumours.

Evidence of clinical relevance

Analyses of human liver metastases from different tumour types confirmed the clinical relevance of the findings: tumours with high numbers of LPL-positive blood vessels also showed increased infiltration by T cells.

“We have uncovered a surprising new mechanism by which the vascular system regulates anti-tumour immunity,” explains study leader Hellmut Augustin.

Co-study leader Mahak Singhal adds: “In many metastatic tumours, T cells fail to gain access to tumour tissue. Our findings suggest that targeted reprogramming of tumour blood vessels could help make such therapy-resistant tumours responsive to immunotherapy.”

Article: LPL-Positive Endothelial Cells Control T-cell Homing in Liver Metastasis

Source: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)