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Single-Cell and Spatial Data Reveals How Hodgkin Lymphoma Cells Evade Immune Attack

In a new study, published in the journal Blood, researchers from the Wellcome Sanger Institute have used single-cell and spatial data to uncover how Hodgkin lymphoma tumours are able to evade the immune system.

In the most comprehensive study on classic Hodgkin lymphoma (cHL) to date, the team has also discovered that high concentrations of certain cell clusters are able to predict which patients are at risk of treatment failure. Their hope is that this knowledge could help identify patients for immune-based therapies in place of more traditional treatments.

The lymphatic system and cancer

Hodgkin lymphoma is a type of cancer that affects the lymphatic system. It occurs when a specific type of B lymphocyte, known as a Reed-Sternberg cell, becomes cancerous. It affects around 2100 people in the UK every year. Traditional cancer treatments are effective in many cases, but not all. High failure rates have meant immunotherapy treatments, such as checkpoint inhibitors, have been used in more recent years to treat certain patients.

When Reed-Sternberg cells become malignant, they express regulatory molecules which prevent T-cell activation. Mononuclear phagocytes near these Read-Sternberg cells also exhibit similar behaviours and their presence is associated with inferior patient outcomes. 

Though there is an understanding that such “tumour-associated macrophages” impact patient outcomes, the details of how this complex network of MNPs interacts with Hodgkin lymphoma has not been investigated in high resolution. The aim of this current study was to look at the tumour microenvironment in unprecedented detail.

Single-cell and spatial data

The team combined single-cell sequencing and spatial transcriptomic data on tumours and healthy lymph node tissues (from the Wellcome Sanger Institute) with multiplexed immunofluorescence imaging data (from Newcastle University). This helped them determine which genes were expressed by which cells and their positions relative to their neighbours.

They found that tumour cells tended to be surrounded by clusters of monocytes, macrophages and cDC2 dendritic cells. From the imaging data, they were able to determine that these cells were expressing molecules to suppress anti-tumour responses.

“This study is a great example of how much information we can get out of one tissue sample,” said Dr Ben Stewart, Postdoctoral Researcher, Wellcome Sanger Institute. “By combining single-cell, spatial transcriptome and histological data, we were able to learn how precisely Hodgkin lymphoma manages to evade immune response. You could think of this approach as a sort of roadmap for molecular pathology, which could be applied to other diseases as well.”

Predicting treatment response

The wealth of information the team were able to gather about these tumour microenvironments allowed them to predict how successful certain treatments would be. One key indicator of successful treatment was if the tumour cells were surrounded by stromal cells. On the other hand, high levels of immune cell clusters were associated with treatment failure. This information could help clinicians to tailor treatments to specific patients and limit the negative effects of chemotherapy, instead progressing to immune-based therapies for certain cohorts.

Another option for treatment is to disrupt the signalling between cancer cells and immune cells to ensure the immune system is able to properly eradicate the cancer. “Single-cell and spatial transcriptomic approaches are bringing a whole new level of detail for the study of human health and disease,” said Dr Sam Behjati, Group Leader & Wellcome Senior Research Fellow, Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust. “When they are combined with other types of data, you can be incredibly specific about what is happening in the human body. This precision is key and I’m sure in time the data that we have generated in this study will have a positive impact on the treatment of Hodgkin lymphoma.”