By Basem M. William, MD

We have made significant progress in our understanding of the pathogenesis and progression of lymphoma through the molecular dissection of malignant cells. By contrast, the importance of the cellular context in which these malignant cells arise and subsequently reside has been relatively neglected until recently. Hodgkin lymphoma (HL) is unique among other lymphomas due to the scarcity of malignant Reed-Sternberg (RS) cells among a matrix of nonmalignant cells. Nearly all patients with HL harbor genetic alterations in 9p24.1, an amplicon carrying the genes for both PD-1 ligands and the JAK2 gene. This leads to augmented JAK/ STAT signaling, increased production of PD-L1 and PD-L2 proteins, and, subsequently, abundant expression of PD-1 ligands on RS cells binding to PD-1 on infiltrating T cells, leading to T-cell inactivation and immune evasion.

In an exciting session on HL, chaired by John P. Leonard, MD, and Susan L. Slager, MD, taking place Saturday at 7:30 a.m. (and again at 4:00 p.m.), Ralf Küppers, MD, of the University of Duisburg-Essen in Germany will walk attendees through a journey of studies from microdissection of HL tumors to whole-exome sequencing of RS cells to reveal the genetic alterations leading to evasion of the immune system. Maher K. Gandhi, MD, of the University of Queensland in Australia will discuss recent developments in understanding the interactions between the malignant RS cells and the tumor microenvironment, including the role of Epstein-Barr virus in driving the immunosuppressive milieu by surface expression of PD-L1 mediated through the NFkB and the JAK-STAT pathways. Barbara Savoldo, MD, of the University of North Carolina at Chapel Hill will discuss a novel CD30-specific chimeric antigen receptor T cell (CAR-T) and report on two phase I/II clinical trials that have produced impressive results. She will elaborate on the prospect of combining CD30-specific CAR-Ts with checkpoint inhibitors to mitigate the deleterious effects of a hostile tumor microenvironment.

In an oral session (Monday, at 7:00 a.m.), two independent groups will report on RNA sequencing on tumor samples from patients with HL showing the pathogenic importance of RS cell–induced CD4+ LAG3+ T cells as a mediator of immunosuppression and a unique gene signature in RS cells that resembles plasma cells with loss of SLAM family receptors, which serve as activation signals for natural killer cells, providing an additional mechanism, beyond those already known, of tumor immune evasion in HL. In another oral session (Saturday, at 10:30 a.m.), Carmelo Carlo-Stella, MD, of the Humanitas University in Italy will present data supporting analysis of circulating tumor mutation- al burden from blood samples of patients with HL using a next-generation sequencing gene panel that seems to predict the response of HL patients to checkpoint inhibitors. We are not there yet, but I see a future where we can identify with precision which patients will respond to a specific therapy out of a blood sample, based on their specific tumor genetics and immune signature.          

Dr. William indicated no relevant conflicts of interest.


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