Immunogenomic Landscape of Hematological Malignancies Mapped

Cancer cells contain proteins that differ from proteins in other tissue. Their components, known as antigens, have to be presented to the T cells of the immune system by the cancer cells.

When they identify antigens, T cells become active and start to destroy cancer cells, which make the latter release more antigens, enhancing the immune response further. In addition to T cells, natural killer (NK) cells have the ability to destroy cells. In immunotherapies, the immune system is therapeutically activated by boosting different stages of the cycle.

A large team of medical scientists collaborating with the Helsinki University Hospital (Helsinki, Finland) integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings. They mapped the immune landscape of hematological malignancies in a dataset covering more than 10,000 patients to identify drug targets and patient groups which could potentially benefit from immunotherapies.

The team reported that infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as V-domain Ig suppressor of T cell activation (VISTA) in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival.

The investigators found that in certain subtypes of acute myeloid leukemia, DNA methylation had epigenetically silenced antigen presentation. A drug that inhibits DNA methylation restored the expression of antigen-presenting proteins in laboratory tests. As the drug is already used to treat acute myeloid leukaemia, it could potentially increase the efficiency of immunotherapies through combined use.

Satu Mustjoki, MD, PhD, a Professor of Translational Hematology and senior author of the study, said, “The extensive survey of the immunogenomic features of hematological malignancies carried out in the study helps scientists and doctors target immunotherapies at the patient groups that gain the most benefit as well as understand the factors that have a potential impact on the efficacy of therapies.”

The authors concluded that their study provided a resource linking immunology with cancer subtypes and genomics in hematological malignancies. The study was published on July 9, 2020 in the journal Cancer Cell.

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