Immunotherapies have revolutionised the treatment of cancer over the past decade, yet clinical experience shows that some patients respond exceptionally well to these treatments while others show almost no effect. This phenomenon has long been studied, with earlier research focusing primarily on the “mutational burden” of tumours — that is, the number of accumulated mutations. A new international study led by researchers from Szeged, however, highlights that the quality of mutations plays an equally important role in determining the immunotherapy response.
The study, published in the journal Molecular Systems Biology, analysed the genetic characteristics of more than 9,300 tumour samples and found that the effects of mutations affecting proteins are not infinitely varied. “Genetic changes can be organised into no more than five characteristic amino acid substitution patterns,” says Dr. Szilvia Juhász, head of the HCEMM Cancer Microbiome Core Group and one of the study’s lead authors. “This means that it is not only the number of mutations in a tumour that matters, but also what types of protein changes they produce and how recognisable they become to the immune system.”
The immune system identifies tumour cells based on the altered protein fragments they produce — known as neopeptides — which are presented to T-cells by HLA molecules on the cell surface. One of the study’s most important findings is that the five identified patterns lead to vastly different degrees of neopeptide recognition by the immune system. “One pattern proved particularly problematic: the protein changes produced by these mutations bind poorly to certain HLA molecules. Since this binding is essential for immune recognition, the tumour can become ‘invisible’ to the immune system. In such cases, an ‘immunologically cold’ microenvironment often develops, resulting in a weaker immunotherapy response — even when the tumour’s mutational burden is high,” explains Dr. Benjamin Papp, a researcher of the Systems Immunology Research Group at HUN-REN Biological Research Centre Szeged and the study’s other main author.
The research also shed light on the fact that an individual’s genetic background significantly influences the “visibility” of a tumour. Certain HLA variants — such as HLA-B*07:02, which is common in Europe — can partially offset the effects of patterns that are poorly recognised by the immune system. “This result reinforces the view that true personalisation of immunotherapies can only be achieved if the genetic characteristics of the tumour and the patient’s genetic background are examined together,” highlighted Dr. Máté Manczinger, head of the Systems Immunology Research Group at HUN-REN SZBK.
The study is an outstanding example of inter-institutional collaboration: the integrated work of the HUN-REN SZBK Systems Immunology Research Group, the HCEMM Cancer Microbiome Core Group, and the Evolutionary Systems Biology Research Group led by Csaba Pál, combined large-scale bioinformatic analysis, immunological interpretation, and an evolutionary perspective. This interdisciplinary approach allowed the researchers to consider not only the mutational burden of tumours, but also qualitative patterns and the patient’s genetic makeup.
“The research may provide a new framework for predicting immunotherapy responses and, in the longer term, contribute to the development of personalised, effective cancer treatments,” summarised Dr. Szilvia Juhász. The study’s findings may form the basis for developing biomarkers for use in clinical practice, enabling faster and more accurate identification of which patients will respond well to various immunotherapy treatments.
Source: https://hun-ren.hu/tudomanyos_kishirek
Img: vecstock. Molecular structure of cancer cells under magnification generated by AI. Freepik
