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New research suggests that the success of immunotherapy for melanoma can be predicted before treatment begins. A common issue with immunotherapies is that a drug that works well in many patients may have little effect in other patients with the same cancer type. But researchers have now identified new markers that can help predict which patients will have a better chance of responding positively to immunotherapy treatments.

The research (undertaken at the Weizmann Institute of Science) was based on the understanding that “learning to predict which treatments are most likely to work is the first step to creating a personalised approach to curing cancer”. The research focused on melanoma, which is often hard to treat and may comprise of varied tumour cells with hundreds of mutations.

Some melanomas have recently been successfully treated with immunotherapy drugs known as checkpoint inhibitors which work by removing obstacles that impede the body’s immune system and prevent it from attacking the cancer. For some patients, checkpoint inhibitor drugs are ineffective.

Researchers analysed data from 470 melanoma patients (via the Cancer Genome Atlas) to understand the differences in response between different people. They were particularly interested in differences in survival rates between patients with an overexpression of subunits of immunoproteasomes, compared to patients with a low expression of these subunits.

The published research explains: [Immunoproteasomes] are a variation on the proteasome subunits normally expressed in most cells (except for immune cells). Proteasomes are protein complexes that function as “cutters”, reducing long proteins to short pieces called peptides. These peptides are later presented on the cells’ surface by molecules called human leucocyte antigens (HLA). HLA peptides are basically bits of “information” – small molecules displayed on the outsides of cells – that “report” about new threats that the immune system needs to assess and address. The immunoproteasome is assembled out of altered subunits and thus produces a unique collection of HLA peptides.

The researchers thought that an overexpression in the collection of HLA peptides might lead to better recognition of the tumour cells by the immune system and therefore a better elimination of cancer cells. They cultured lines of tumour cells from melanoma patients and then overexpressed the immunoproteasome subunits and identified the HLA peptides presented. By testing the response of the immune cells from the same patients, they showed that the newly formed HLA peptides were indeed more reactive compared to the HLA peptides presented by cells without this overexpression.

Could two subunits the research identified in particular and the unique HLA-bound peptides these produce be a predictor of immunotherapy success? The experiments showed that in tumour cells in which the subunits were overexpressed, the various immune system components that directly fight the cancer were more prevalent and more active than average. Indeed, looking back at the details of cancer patients in the database, [researchers] reported that the expression levels of the two subunits were excellent predictors of the outcome – better than the tumour mutational burden, a biomarker that is currently used in the clinic.

The research suggests that expression of the immunoproteasome may be used as a biomarker for predicting better outcomes in melanoma and may improve clinicians’ ability to match patients to immunotherapies.

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Source: Press release