Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-g release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma. Cancer Res; 73(2); 652-61. Ó2012 AACR.
During one year, 55 bone marrow biopsies from 49 patients with CDC-defined acquired immune deficiency syndrome (AIDS) were studied. Eighty-three percent were normocellular or hypercellular; 17% were hypocellular. Marrow plasma cells were increased in 83% of patients, most showing polyclonal hypergammaglobulinemia. Forty percent of patients showed peripheral neutropenia, 29% thrombocytopenia, and 79% lymphopenia with markedly reduced T4+ lymphocytes. Eighty-five percent of patients were anemic, with iron studies showing a pattern consistent with the anemia of chronic disease. Mycobacterium avium-intracellulare (MAI) grew from ten (20%) biopsies, four with granuloma and six without granuloma (five of these six also showed marrow hypocellularity). Small poorly formed granuloma (70-150 micron) were seen in eight (16%) patients (four AFB-culture positive, 4 negative). Three of four granuloma-positive, culture-negative cases eventually grew MAI from autopsy material. Five (10%) patients had lymphoplasmacytic aggregates; later, one developed lymphoma, another, markedly atypical lymphoid hyperplasia. Two additional patients showed marrow B-cell lymphomas. Of these findings, only marrow MAI meets the CDC definition of AIDS. However, in this series, small ill-defined granulomas, lymphoplasmacytic aggregates, and B-cell lymphomas also were found. The authors conclude that these latter findings, when seen in high-risk patients, particularly those with lymphopenia, anemia, and/or hypergammaglobulinemia, also strongly suggest the diagnosis of AIDS.
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