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Study Spells Out Immune, Genomic, Epigenomic Interactions in Hematological Malignancies

NEW YORK – A Finnish research team has started to trace the immune shifts that coincide with the presence of hematological malignancies such as multiple myeloma, lymphoma, leukemia, or myelodysplastic syndrome in an effort to better understand the biology of the conditions as well as potential immune-based treatment strategies.

"Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development," co-senior authors Satu Mustjoki, a hematology and translational immunology researcher affiliated with the Helsinki University Hospital, the University of Helsinki, and iCAN Digital Prevision Cancer Medicine Flagship, and Merja Heinaniemi, a biomedicine researcher at the University of Eastern Finland, and their colleagues wrote, noting that their Cancer Cell study, published Thursday, "provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies." 

With the help of array-based gene expression profiles generated for cell type-sorted and -unsorted samples for the Hemap gene expression resource, the researchers considered transcriptomic patterns present in almost 8,500 samples spanning three-dozen types of hematological malignancies and corresponding tumor microenvironments, comparing them to those found in hundreds of normal hematological samples or cell lines.

Along with follow up RNA sequencing and single-cell RNA-seq experiments to validate apparent immune and tumor interactions in more than 100 acute myeloid leukemia (AML) and MDS samples, the team analyzed "multi-omic" datasets encompassing somatic mutation, copy number, expression, methylation, clinical and other data for nearly 2,400 more diffuse large B-cell lymphoma, AML, multiple myeloma, or related cell line samples profiled for the Cancer Genome Atlas, CoMMpass, BeatAML, and other projects.

Broadly speaking, the authors explained, results from the tumor and immune analyses "underline the importance of integrating data of genetic and epigenetic aberrations, as well as the tumor microenvironment, for a complete understanding of factors that may impact immunotherapy responsiveness."

Within MDS-related AML cases marked by TP53 mutations, for example, the researchers saw signs of cytotoxic T cell and natural killer cell infiltration. The enhanced cytolytic lymphocyte infiltration appeared to be shared somewhat in cases of activated B cell-like diffuse large B-cell lymphomas, though the lymphomas tended toward interferon-gamma-related immune signatures.

When the team considered the methylation patterns found across hematological malignancies, it uncovered epigenetic features influencing the antigen flags going up in certain blood conditions, while integrated analyses that included gene expression data pointed to immune targets that may be amenable to treatment in certain cancer types. In myeloid malignancies, for example, the analyses revealed enhanced expression of an immune checkpoint containing the VISTA protein, whereas other conditions had more pronounced expression of the PD-L1 or CD70 immune checkpoints.

Together, these and other features found in the analyses offered clues to patient outcomes and survival, the authors wrote, supporting the importance of including immunological properties — along with genetic and epigenetic profiles — in prognostic prediction models.

"[O]ur integrative analysis provides evidence of genomic and microenvironmental factors associated with variation in the immune contexture between different tumors," they wrote, arguing that the results "highlight the need to integrate genetic, epigenetic, and transcriptomic data of different aspects of the immune landscape to understand potential determinants of responsiveness to cancer immunotherapies."