The classical Hodgkin lymphoma tumor microenvironment: macrophages and gene expression-based modeling

Despite the high cure rate in classical Hodgkin lymphoma (CHL), more accurate tailoring of upfront treatment is required to maximize cure while avoiding unnecessary short- and long-term treatment side effects. To this end, the unique tumor microenvironment of CHL has been searched extensively for prognostic biomarkers. Beyond targeted immunohistochemistry (IHC) studies, gene expression profiling (GEP) of diagnostic whole tissue biopsies has allowed a de novo approach to biomarker discovery. Among numerous candidate biomarkers, an association between the number of tumor-associated macrophages in the microenvironment and outcomes after ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) chemotherapy emerged, and multiple subsequent studies have validated this biological relationship using IHC. These studies have also defined key aspects for macrophage interrogation, including the characteristics of the CD68 and CD163 antibodies, appropriate scoring methodologies, and the identification of specific patient populations in which macrophage IHC may not be prognostic. The GEP studies also led to the development of gene expression-based prognostic models for advanced-stage CHL, with new technologies allowing reliable gene expression quantitation using RNA from routinely produced formalin-fixed paraffin-embedded biopsies. The bridge to predictive biomarkers that can be used reliably to inform upfront treatment selection requires further studies to demonstrate that these biomarkers can identify robustly, at diagnosis, patients at high risk of treatment failure with ABVD and that this risk may be overcome using alternative treatments.