Expression of CD137 on Hodgkin and Reed–Sternberg Cells Inhibits T-cell Activation by Eliminating CD137 Ligand Expression

Abstract

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.

Involvement of the 4-1BB/4-1BBL Pathway in Control of Monocyte Numbers by Invariant NKT Cells

“…Lack of increase in 4-1BBL expression on monocytes in these doublets could be due to these molecules being upregulated later than 4-1BB, so that overall 4-1BBL expression was increased in the monocyte population but not on contacting (doublet) cells. Alternatively, 4-1BBL could be endocytosed and internalized at this time point, as found on CD137L-expressing Hodgkin's disease cell line KM-H2 (34). Induction of 4-1BB and 4-1BBL with and without direct antigenic stimulation and indirectly via inflammatory signals from IAV infection implicates this pathway in iNKT-monocyte interactions at steady state and during viral infection.…”

4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy

“…Expression of 4-1BB in cancer patients was found also on tumor vessel walls, on the endothelial wall, on vascular smooth muscles (20), and in liver tissue (21). Interestingly, constitutive and functional expression of 4-1BB was also noted on leukemic cell lines (22), and in some cases, such expression has been known to curb T cell activation (23), and is therefore considered as a possible anti-tumor agent (24). Like certain members of the TNFR superfamily, 4-1BB and 4-1BBL also exist in soluble forms in the sera of patients suffering from certain clinical conditions, including cancer.…”

Prognostic Biomarkers for Hodgkin Lymphoma

“…result of down-regulation of CD137L [80,81]. In this model, binding of CD137 to its ligand CD137L on the same cell induces internalization of the complex and downregulation of the co-stimulatory ligand.…”

“…The inclusion of this co-stimulatory pathway in immunological cancer therapy concepts has been suggested [79]. Interestingly, HL cells can express the receptor CD137 [80,81].…”