Melanoma, one of the deadliest forms of skin cancer, affects an estimated 330,000 people worldwide each year and causes nearly 60,000 deaths annually.

While early-stage melanoma is one of the most curable cancers, later-stage melanomas can present significant difficulties in treatment due to therapy resistance.

Even though immune therapy treatments such as immune checkpoint blockade (ICB) therapies have transformed cancer treatment, around half of patients with advanced melanoma do not respond to these therapies.

Now, a study conducted by researchers from the VIB-KU Leuven Centre for Cancer Biology uncovered that ‘natural killer’ (NK) cells may actually be contributing to tumour resistance in patients who don’t respond to ICB.

In the study, led by Prof. Jean-Christophe Marine, researchers collected tumour biopsies from melanoma patients both before and shortly after initiating ICB therapy.

Using advanced spatial omics technology, they precisely mapped the location of different immune cells within the tumour microenvironment.

Strikingly, they found that in patients who did not respond to treatment, there was a significant early increase in cytotoxic NK cells.

However, these cells were positioned at the tumour’s periphery rather than infiltrating its core.

In contrast, tumours that responded to ICB therapy showed a different immune landscape, with NK cells located inside the tumour bed alongside CD8 T cells, the immune system’s primary tumour-attacking cells.

To further investigate why NK cells were acting in this manner, the team developed a mouse model in which immune cells were unable to infiltrate melanoma tumours – just like seen in many patients resistant to ICB immunotherapy – and where they could pharmacologically deplete NK cells.

The result: CD8 T cells were suddenly able to infiltrate the tumour core and the tumour was cleared once ICB was administered.

Additionally, further analysis revealed that NK cells are actively recruited to block access to the tumour via the CX3CR1 chemokine receptor.

A grand challenge

The study, which was published in the renowned journal Cancer Discovery, is a direct result of the Pointillism project, an initiative under the umbrella of VIB’s Grand Challenges Programme.

The goal of the project was to apply single-cell multi‑omics and spatial profiling to dissect the cellular and molecular landscape of tumours with high precision.

In its first phase, the project identified candidate biomarkers that may predict which melanoma and breast cancer patients respond to immune‑checkpoint blockade (ICB) therapy.

In a next phase, the newly launched Pointillism 2.0 project will look at validating and combining biomarkers to develop a high-performance biomarker panel, potentially in the form of a blood test, to quickly and accurately determine a patient’s likelihood of responding to ICB.

Source: Vlaams Instituut voor Biotechnologie