Sézary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-β on the cell surface

Abstract

IntroductionCutaneous T-cell lymphomas (CTCLs) comprise a spectrum of malignant clonal proliferation of T lymphocytes with a predilection for skin involvement, and which have an increasing incidence. 1 CTCL presents commonly as mycosis fungoides (MF) and rarely as the leukemic variant, Sézary syndrome (SS); malignant cells in these disorders display effector/memory and central/memory T-cell phenotype, respectively. 2 CTCL cells are typically positive for CD4, CD45RO, cutaneous lymphocyteassociated antigen (CLA), and CC chemokine receptors (CCRs), but negative for CD7 and CD26. 3 Because existing treatments for CTCL rarely achieve complete remissions, especially for patients with advanced MF and SS, [4][5][6] it is important to better understand pathogenesis, identify more specific diagnostic markers, and develop better treatments.T-cell activation is dependent on signals delivered by antigen presenting cells (APCs) to the antigen (Ag)-specific T-cell receptor (TCR) and to accessory receptors on T cells. Accessory receptors can be costimulatory or coinhibitory. A costimulatory signal is transmitted by CD80 or CD86 on APCs to the CD28 receptor on T cells. By contrast, a variety of molecules transmit coinhibitory signals including programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2 7,8 ; B-and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator; 9,10 and Tim-3 ligand/Galectin-9 and Tim-3. 11,12 Different types of tumors have been shown to express PD-L1, 13 and malignant cells of acute myeloid leukemia and CTCL were reported to overexpress cytolytic T lymphocyte-associated antigen 4 (CTLA-4), 14,15 thereby suggesting that tumors can use coinhibitory molecules to suppress host antitumor immunity.The dendritic cell-associated heparan sulfate proteoglycanintegrin ligand (DC-HIL) is a type I transmembrane receptor (95-120 kDa) expressed constitutively at high levels by many different APCs and at lower levels by particular nonlymphoid cells. 16 DC-HIL is also known as glycoprotein nmb, 17 osteoactivin, 18 and hematopoietic growth factor-inducible neurokinin-1 type. 19 We have shown DC-HIL to bind heparan sulfate (HS) chains on syndecan-4 (SD-4) expressed on activated (but not resting) T cells, and this binding attenuates strongly TCR-induced activation. [20][21][22] Activated T cells appear to express unique HS on this SD-4 because DC-HIL does not bind to B cells that also express SD-4 constitutively at high levels.Having shown SD-4 to be expressed primarily by effector and memory T cells, 21 we suggested that CTCL cells also express it. Indeed, we found SD-4 to be overexpressed by CTCL cell lines and by malignant T cells in patients with SS, whereas T cells from healthy controls and patients with atopic dermatitis or psoriasis did not. Moreover, SD-4 on CTCL cell lines and SS cells featured distinct HS moieties at levels much greater than levels expressed by normal T cells activated in vitro. These HS moieties were responsible for the ability of SD-4 to inhibit activation of T cells via the followi...

Bortezomib Inhibits Expression of TGF-β1, IL-10, and CXCR4, Resulting in Decreased Survival and Migration of Cutaneous T Cell Lymphoma Cells

“…Several studies have shown that CTCL patients have decreased expression of TβRI and/or TβRII, and reduced responsiveness to the growth-inhibitory effects of TGFβ1 (59–64). We have detected TβRI and TβRII in all three CTCL lines, even though Hut-78 and HH cells express considerably lower protein levels of both receptors than H9 cells (Fig.…”

The type III TGFβ receptor regulates filopodia formation via a Cdc42-mediated IRSp53–N-WASP interaction in epithelial cells

“…Ligand binding to TβRII leads to recruitment of TβRI and activates TβRI kinase activity which can initiate Smad and non-Smad signaling pathways [42]. TGF-β induces actin cytoskeleton mobilization in cells, and these effects appear to be dependent upon non-Smad signaling [43, 44]. TGF-β can also activate Cdc42 [43] [18].…”

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

“…As noted above, malignant CTCL cells impair DC maturation and activation of benign T cells in an IL-10-dependent manner. Similarly, TGF-β was reported to enhance the malignant T cells’ ability to inhibit activation of syngenic and allogenic normal T cells [66–68, 109]. Given the potent immunosuppressive capacities of IL-10 and TGF-β, it could be expected that they would also inhibit the proliferation and cytokine production of the malignant T cells in an autocrine fashion.…”