A new study suggests that the way immune cells are organised inside melanoma tumours may help researchers better understand which patients will benefit from combination immunotherapy after standard anti-PD-1 treatment stops working — and which may not.

The findings, published in Cancer Discovery, a journal of the American Association for Cancer Research, show that patients whose tumours contained active networks of cancer-killing T cells were more likely to benefit from treatment, while those with dense clusters of plasma cells were far less likely to benefit.

Why it matters 

Anti-PD-1 drugs have become the backbone of treatment for advanced melanoma by helping the immune system recognise and attack cancer cells.

But many tumours eventually stop responding or never respond at all. When that happens, doctors often turn to another type of immunotherapy, anti-CTLA-4.

Even then, only about 30% of patients see meaningful benefit. Researchers have long known that tumours with more immune activity tend to respond better.

What has been less clear is why some tumours remain resistant, even when a second immune drug is added, and whether there is a way to identify those cases earlier.

What the study did

To address this question, researchers analysed tumour biopsies from patients enrolled in the SWOG S1616 clinical trial.

All had melanoma that had already progressed on anti-PD-1 therapy. Patients were randomly assigned to receive either a combination of two immunotherapies — ipilimumab (which targets CTLA-4) and nivolumab (which targets PD-1) — or ipilimumab alone.

Tumour biopsies were taken before treatment and again about a month later. Working with collaborators at the Parker Institute for Cancer Immunotherapy and industry partners, the team combined genetic sequencing with high-resolution imaging to map not just which genes were active in the tumours, but where different immune and cancer cells were physically located.

What they found

The researchers found that tumour genetics alone did not explain which patients responded to treatment. Instead, the most important differences were seen in the tumour’s immune environment.

In patients who responded to combination therapy, CD8 T cells, the immune system’s primary cancer-killing cells, were able to enter the tumour and cluster closely around melanoma cells.

These tumours also showed evidence of active immune signalling, with different CD8 T cell populations present, including cells actively dividing near tumour cells.

As tumours began to shrink, additional immune cells such as regulatory T cells and monocytes, also appeared in the tumour microenvironment.

Rather than acting in isolation, immune and cancer cells formed organised patterns of interaction, often referred to as cellular neighbourhoods, where different cell types work together within specific regions of the tumour.

In contrast, tumours that did not respond to treatment often contained dense clusters of plasma cells.

These plasma cell-rich regions were associated with reduced T cell activity and continued tumour growth, suggesting they may be linked to a tumour environment that is less able to support an effective immune attack.

The study also highlights why the physical location of immune cells inside a tumour is so important.

The researchers found that T cells in responding tumours were positioned near blood vessels and other supportive immune cells, allowing them to move into the tumour and coordinate an effective attack.

“The T cells need to directly see the cancer cells to kill them, but they also need to be able to move around and get the correct signals to tell them to keep going or keep killing,” said Dr. Katie Campbell, adjunct assistant professor of medicine at the David Geffen School of Medicine at UCLA and first author of the study.

“If they can’t get into the tumour through blood vessels, or don’t get these signals because the right types of immune cells aren’t there, the patient isn’t going to respond to the therapy.”

What this means for patients

The findings suggest it may eventually be possible to use tumour structure, not just genetics, to help guide treatment decisions in melanoma, identifying patients most likely to benefit from combination immunotherapy and those who may need a different treatment approach sooner.

What’s next

Researchers say the next step is figuring out how to reshape the tumour environment in patients whose cancers resist immune attack, and how to better combine immunotherapy with treatments such as targeted therapy, chemotherapy or radiation to improve response rates.

Article: Cellular neighborhoods govern antitumor T-cell infiltration following anti-CTLA-4 in melanoma with primary resistance to anti-PD-1

Source: University of California - Los Angeles Health Sciences