20 February 2023

A new study into classic Hodgkin’s lymphoma could accelerate the use of precision medicine and identify patients who could benefit from immunotherapies, British researchers have reported.

The research team was jointly led by scientists from the Wellcome Sanger Institute, Cambridge and Newcastle University. Their study – the most comprehensive yet into the disease – found that cancer cells use signals to attract certain types of immune cell and instruct them not to attack.

Publishing in the journal Blood, the team also found that high concentrations of these cell clusters predicted the failure of chemotherapy.

Although most Hodgkin’s lymphoma patients respond well to chemotherapy, radiotherapy or a combination of both, the treatments fail for some. However, they often respond well to new treatments such as immune checkpoint inhibitors, especially PD-1 blockers.

For this study, researchers combined multiple approaches to investigate in unprecedented detail the immune microenvironment around Hodgkin’s lymphoma tumours.

They generated single-cell sequencing and spatial transcriptomic data from Hodgkin’s lymphoma and healthy lymph node tissue, to identify the genes expressed by each cell and their position in relation to their neighbours. This was combined with microscope imaging data from Hodgkin’s lymphoma biopsies from Newcastle University.

When they analysed single-cell data, it showed cancer cells were surrounded by clusters of macrophages, monocytes and cDC2 dendritic cells. Imaging data went on to show these cells expressed molecules that suppressed their anti-tumour capabilities.

First study author Dr Ben Stewart, of the Wellcome Sanger Institute, said: “This study is a great example of how much information we can get out of one tissue sample. By combining single-cell, spatial transcriptome and histological data, we were able to learn how precisely Hodgkin’s lymphoma manages to evade immune response.”

The research team discovered two distinct microenvironments around cancer cells that indicated how successful traditional treatments would be.

They found high concentrations of immune cell clusters around cancer cells were predictive of treatment failure. In contrast, a microenvironment with high concentrations of stromal cells was associated with treatment success.

The authors believe that because stromal cells indicate that tissue has been previously repaired, it is possible the immune system had already been partially successful in fighting the disease, with treatment helping to eradicate the cancer.

Joint senior author Dr Chris Carey, from Newcastle University, said: “Understanding how Hodgkin’s lymphoma tumours bypass the body’s immune response opens up new possibilities to treat this disease. If we could identify which patients have higher concentrations of these immune cell clusters around the tumour, for example, we could tailor their treatments, limiting the effects of chemotherapy for patients in whom it is less likely to work and proceeding directly to immune-based therapies that stand a better chance.”

The cellular messaging used by the cancer cells to manipulate immune cells is also a potential drug target. Disrupting this signalling would in theory allow the immune system to respond as it should and attack the cancer cells.

Joint senior study author Dr Sam Behjati, from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, added: “Single-cell and spatial transcriptomic approaches are bringing a whole new level of detail for the study of human health and disease.

“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’s lymphoma.”

Source: Stewart BJ, Fergie M, Young M, Jones C, Sachdeva A, Blain AE, Bacon CM, Rand V, Ferdinand JR, James KR, Mahbubani KT, Hook CE, Jonas N, Coleman N, Saeb-Parsy K, Collin M, Clatworthy M, Behjati S, Carey CD.  (2023) “Spatial and molecular profiling of the mononuclear phagocyte network in Classic Hodgkin lymphoma.” Blood, doi: 10.1182/blood.2022015575

Link: https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2022015575/494363/Spatial-and-molecular-profiling-of-the-mononuclear 

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