CD30

Overview

First described 1992. Earliest sequence paper UniProt cites for the protein: Duerkop et al, Cell, 1992, "Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin's disease". Source.

• Lymphoma: Essentially every Reed-Sternberg cell of classical Hodgkin lymphoma, anaplastic large cell lymphoma, a subset of peripheral T-cell lymphoma and of primary mediastinal B-cell lymphoma, and lymphomatoid papulosis. Also on healthy cells: Activated T and B cells, and monocytes: the Human Protein Atlas reads TNFRSF8 as lineage enriched in monocytes (97 nTPM). Resting lymphocytes do not carry it, which is why CD30 is the closest thing in lymphoma to a tumour-restricted antigen in an adult. What the medicine does: CD30 signals to NF-kB through TRAF proteins and internalises, so it carries the conjugate brentuximab vedotin. The free antigen is also shed into serum, which complicates attempts to use it as a blood marker. How tumours lose it: Loss of CD30 at relapse after brentuximab vedotin has been reported but is not the dominant mechanism; failure is more often payload-related or driven by the microenvironment. What that costs the patient: Peripheral neuropathy, cumulative and dose-limiting, from the auristatin payload; neutropenia; and, rarely, progressive multifocal leukoencephalopathy. Unlike the B-cell antigens, CD30 blockade does not empty a whole normal compartment, so there is no equivalent of B-cell aplasia.
• Lymphoma, The Hodgkin microenvironment, where the cancer cell is a minority: A classical Hodgkin lymph node is mostly not cancer. The Hodgkin and Reed-Sternberg cells are a small minority of the tissue, surrounded by T cells, eosinophils, plasma cells, macrophages and fibrosis that the tumour recruits and then uses. Their identity was only settled by picking single cells off a histological section with a micromanipulator and amplifying the immunoglobulin genes: each case gave a single clonal heavy-chain rearrangement, proving that the scattered giant cells are one clone of B-lineage origin even though they have lost almost every B-cell marker (Kuppers 1994). Because the malignant cells are so rare, bulk genomic assays on a Hodgkin biopsy mostly measure the infiltrate, which is why the 9p24.1 work needed laser capture and fluorescence in situ hybridisation rather than sequencing. Frequency: An increased number of CD68-positive macrophages, measured by immunohistochemistry in an independent cohort of 166 patients, tracked shorter progression-free survival, a higher chance of relapse after autologous transplant and shorter disease-specific survival, and outperformed the International Prognostic Score in multivariable analysis (Steidl 2010). What it changes about treatment: No test on the infiltrate is used to choose treatment. The practical consequences are methodological: a Hodgkin biopsy needs enough tissue for architecture, a core needle sample is often not enough, and interim PET rather than a molecular marker is what the treatment is adapted to.
• Lymphoma, Epstein-Barr virus and its latency programmes: Epstein-Barr virus persists for life in the memory B-cell pool of almost everyone, and what it expresses while it is there decides what it can cause. In latency I only EBNA1 is made, which is enough to keep the episome but gives the immune system almost nothing to see; this is the Burkitt pattern, where the virus coexists with a MYC translocation. In latency II, EBNA1 with LMP1 and LMP2, LMP1 mimics a permanently engaged CD40 receptor and drives NF-kB; this is the Hodgkin and NK/T-cell pattern. In latency III the full set of nuclear antigens and membrane proteins is expressed and will immortalise a resting B cell outright, which is what happens when T-cell surveillance is removed, as in post-transplant lymphoproliferative disorder and HIV-associated lymphoma. The virus was found in the first place by electron microscopy of cells cultured from Burkitt lymphoma, whose geographic distribution matching holoendemic malaria had suggested a viral cause (Young and Rickinson 2004). Frequency: The share of each disease that is EBV-positive varies by subtype, by geography and by age, and this layer does not state a single figure because the published ranges are wide and cohort-dependent. What is consistent is the direction: the proportion rises with immunosuppression and with age, and endemic Burkitt lymphoma in equatorial Africa is almost uniformly positive while sporadic Burkitt lymphoma usually is not. What it changes about treatment: Reducing immunosuppression is the first treatment of post-transplant lymphoproliferative disorder, which is the only place where acting on the virus changes the plan. Plasma EBV DNA is used to monitor response in NK/T-cell lymphoma and in post-transplant disease. EBV-specific T cells are licensed for post-transplant disease after transplant failure.