A recent study published in Molecular Systems Biology highlights how specific mutation patterns in tumors can enhance or diminish their visibility to the immune system. Researchers from the HUN-REN Szeged Biological Research Centre and HCEMM assert that the characteristics of mutations are crucial for understanding immunotherapy effectiveness, rather than focusing solely on the number of mutations present.
The research team identified five recurring protein mutation patterns, referred to as amino acid substitution signatures, that significantly influence how tumors interact with the immune system. By analyzing nearly 9,300 cancer genomes from various types of cancer, the study revealed that these patterns, rather than random mutations, dominate the genetic landscape of tumors.
Understanding Tumor Visibility and Immune Response
The findings suggest that certain mutation patterns lead to the formation of highly immunogenic protein fragments known as neoantigens. These fragments are critical for alerting immune cells and enabling them to recognize and attack tumors. Conversely, other patterns generate less recognizable neoantigens, leading to what are termed “cold” tumors that can effectively evade immune detection.
Dr. Szilvia Juhász, Head of the Cancer Microbiome Research Group at HCEMM and a lead author of the study, noted, “Despite the diversity of mutational processes, their protein-level consequences converge into just five recurring fingerprints, which can strongly influence immune recognition.” This insight emphasizes the importance of mutation patterns in shaping the immune response to tumors.
One notable discovery involved a specific mutational pattern associated with DNA repair defects and chemical exposures. Tumors exhibiting this pattern tend to show poor responses to immune checkpoint inhibitor therapies, even if they carry a high overall mutational burden. Dr. Benjamin Papp, a researcher at the HUN-REN Szeged Biological Research Centre and co-first author of the study, stated, “Mutational burden alone is insufficient. Qualitative, protein-level consequences of mutations are critical for understanding why immunotherapy fails in many patients.”
Implications for Personalized Immunotherapy
The study also explored how certain genetic variants in the human immune system, particularly specific HLA class I types prevalent in Europeans, can influence the visibility of tumors to T cells. This finding indicates that the same tumor might be perceived differently by the immune system depending on a patient’s genetic background.
Dr. Máté Manczinger, Head of the Systems Immunology Research Group at the HUN-REN Szeged Biological Research Centre and senior author of the study, emphasized the need for a refined framework for predicting immunotherapy responses. “Tumor visibility to the immune system is not determined by mutation numbers alone, but also by the protein-level patterns those mutations create,” he explained.
These findings pave the way for more personalized approaches to immunotherapy, potentially reducing the risk of unnecessary treatments and side effects. By accurately predicting therapy responses, healthcare providers can shorten the time it takes to identify effective therapies tailored to individual patients.
The collaborative effort behind this study involved the Systems Immunology Research Group at the HUN-REN Szeged Biological Research Centre, the HCEMM Cancer Microbiome Research Group, and contributions from the Evolutionary Systems Biology Research Group led by Csaba Pál. The research underscores the intricate relationship between tumor genetics and immune system interactions, marking a significant step toward advancing cancer treatment strategies.
