“… 32 CD30 (see below) and TNFα were chosen for HL cell lines as they are expressed by these cells ( Figure 5A , B ) and are substrates for ADAM10 and/or ADAM17. 33 , 34 Figure 5. ExoV contribute to CD30 shedding and are inhibited by LT4 or CAM29 .…”
Section: Resultsmentioning
confidence: 99%
“…ADAM10 inhibitors reduce the shedding and maintain the expression of CD30 on HL cells increasing the biological effect of the ADC Btx Ved and the humanized anti-CD30 Iratumumab . As CD30 is a reported substrate for ADAM10 and is also a target for immunotherapy, 19 , 32 , 34 , 35 we first analyzed the effect of ExoV on CD30 shedding from L540 and L428 cells and the possible counteracting action of ADAM10 inhibitors. In Figure 5A and B expression of CD30 on L428 cells and their ExoV is shown, compared to MSC16412 and related ExoV that are CD30 negative.…”
Section: Resultsmentioning
confidence: 99%
“…Thus, the cross-talk occurring between stromal and cancer cells in the HL microenvironment, due to exosome-like microvesicles and ADAM10 activity, can result in the release of cytokines, as TNFα, described as lymphoma growth factor, 34 or soluble molecules, such as sMICA or sCD30, that potentially interfere with host immune response, or with ADC-based immunotherapy. 14-18 , 33 ADAM10 blockers can interfere with such process, allowing the development of an anti-lymphoma immune response and/or an efficient ADC-based or humanized Ab-immunotherapy ( Figure 7 ).…”
Shedding of ADAM10 substrates, like TNFα, MICA or CD30, is reported to affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. Soluble forms of these molecules and ADAM10 can be carried and spread in the microenvironment by exosomes released by tumor cells. We reported new ADAM10 inhibitors able to prevent MICA shedding in Hodgkin lymphoma (HL), leading to recognition of HL cells by cytotoxic lymphocytes.In this paper, we show that the mature bioactive form of ADAM10 is released in exosome-like vesicles (ExoV) by HL cells and lymph node mesenchymal stromal cells (MSC). We demonstrate that ADAM10 inhibitors are released in ExoV by MSC or HL cells, endocytosed by bystander cells and localized in the endolysosomal compartment in HL MSC. ExoV released by HL cells can enhance MICA shedding by MSC, while ExoV from MSC induce TNFα or CD30 shedding by HL cells. Of note, ADAM10 sheddase activity carried by ExoV is prevented with the ADAM10 inhibitors LT4 and CAM29, pretreating either the ExoV-producing or the ExoV-receiving cells. In particular, both inhibitors reduce CD30 shedding maintaining the anti-tumor effects of the ADC Brentuximab-Vedotin or the anti-CD30 Iratumumab on HL cells.Thus, spreading of ADAM10 activity due to ExoV can result in the release of cytokines, like TNFα, a lymphoma growth factor, or soluble molecules, like sMICA or sCD30, that potentially interfere with host immune surveillance or immunotherapy. ADAM10 blockers can interfere with this process, allowing the development of anti-lymphoma immune response and/or efficient ADC-based or human antibody-based immunotherapy.
“… 32 CD30 (see below) and TNFα were chosen for HL cell lines as they are expressed by these cells ( Figure 5A , B ) and are substrates for ADAM10 and/or ADAM17. 33 , 34 Figure 5. ExoV contribute to CD30 shedding and are inhibited by LT4 or CAM29 .…”
Section: Resultsmentioning
confidence: 99%
“…ADAM10 inhibitors reduce the shedding and maintain the expression of CD30 on HL cells increasing the biological effect of the ADC Btx Ved and the humanized anti-CD30 Iratumumab . As CD30 is a reported substrate for ADAM10 and is also a target for immunotherapy, 19 , 32 , 34 , 35 we first analyzed the effect of ExoV on CD30 shedding from L540 and L428 cells and the possible counteracting action of ADAM10 inhibitors. In Figure 5A and B expression of CD30 on L428 cells and their ExoV is shown, compared to MSC16412 and related ExoV that are CD30 negative.…”
Section: Resultsmentioning
confidence: 99%
“…Thus, the cross-talk occurring between stromal and cancer cells in the HL microenvironment, due to exosome-like microvesicles and ADAM10 activity, can result in the release of cytokines, as TNFα, described as lymphoma growth factor, 34 or soluble molecules, such as sMICA or sCD30, that potentially interfere with host immune response, or with ADC-based immunotherapy. 14-18 , 33 ADAM10 blockers can interfere with such process, allowing the development of an anti-lymphoma immune response and/or an efficient ADC-based or humanized Ab-immunotherapy ( Figure 7 ).…”
Shedding of ADAM10 substrates, like TNFα, MICA or CD30, is reported to affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. Soluble forms of these molecules and ADAM10 can be carried and spread in the microenvironment by exosomes released by tumor cells. We reported new ADAM10 inhibitors able to prevent MICA shedding in Hodgkin lymphoma (HL), leading to recognition of HL cells by cytotoxic lymphocytes.In this paper, we show that the mature bioactive form of ADAM10 is released in exosome-like vesicles (ExoV) by HL cells and lymph node mesenchymal stromal cells (MSC). We demonstrate that ADAM10 inhibitors are released in ExoV by MSC or HL cells, endocytosed by bystander cells and localized in the endolysosomal compartment in HL MSC. ExoV released by HL cells can enhance MICA shedding by MSC, while ExoV from MSC induce TNFα or CD30 shedding by HL cells. Of note, ADAM10 sheddase activity carried by ExoV is prevented with the ADAM10 inhibitors LT4 and CAM29, pretreating either the ExoV-producing or the ExoV-receiving cells. In particular, both inhibitors reduce CD30 shedding maintaining the anti-tumor effects of the ADC Brentuximab-Vedotin or the anti-CD30 Iratumumab on HL cells.Thus, spreading of ADAM10 activity due to ExoV can result in the release of cytokines, like TNFα, a lymphoma growth factor, or soluble molecules, like sMICA or sCD30, that potentially interfere with host immune surveillance or immunotherapy. ADAM10 blockers can interfere with this process, allowing the development of anti-lymphoma immune response and/or efficient ADC-based or human antibody-based immunotherapy.
“…Possible major drawbacks of this therapeutic approach might be the accessibility of ADAM10 + cells at the tumor site, that we show to be abundant according to immunohistochemistry, 16 and the inhibition of cleavage of other ADAM10 substrates. Nevertheless, it is conceivable that effector lymphocytes resident in the LN can be activated and exert antitumor activity; furthermore, inhibition of cleavage of other ADAM10 substrates, such CD30, a target for antibody-based anti-lymphoma therapy, 34 or TNFα, a reported growth factor for lymphomas, 35 might also be useful in HL.…”
Hodgkin lymphoma (HL) resistant to conventional therapies is increasing, making of interest the search for new schemes of treatment. Members of the “A Disintegrin And Metalloproteases” (ADAMs) family, mainly ADAM10 or ADAM17, have been proposed as therapeutic targets in solid tumors and some ADAMs inhibitors have been shown to exert antitumor effects. We have previously described an overexpression of ADAM10 in HL, together with increased release of NKG2D ligands (NKG2D-L) and reduced activation of effector T lymphocytes with anti-lymphoma capacity. Aim of the present work was to verify whether inhibition of ADAM10 in HL cells could restore the triggering of NKG2D-dependent anti-lymphoma T cell response. As no selective ADAM10 blockers have been reported so far, we synthesized the two hydroxamate compounds LT4 and MN8 with selectivity for ADAM10 over metalloproteases (MMPs), LT4 showing higher specificity for ADAM10 over ADAM17. We show that (i) HL lymph nodes (LN) and cultured HL cells express high levels of the mature active membrane form of ADAM10; (ii) ADAM10 is the major sheddase for the NKG2D-L in HL cells; (iii) the new LT4 and MN8 compounds strongly reduce the shedding of NKG2D-L by HL cell lines and enhance the binding of NKG2D receptor; (iv) of note, these new ADAM10 inhibitors increase the sensitivity of HL cell lines to NKG2D-dependent cell killing exerted by natural killer and γδ T cells. Overall, the biologic activity of LT4 and MN8 appears to be more potent than that of the commercial inhibitor GI254023X.
“…The signaling of TNFR2 is responsible for the accumulation and survival of MDSCs through upregulation of cellular FLICE-inhibitory protein and inhibition of caspase-8 activity ( 3 ). Moreover, TNFR2 is also expressed by tumor cells, including colon cancer ( 38 ), Hodgkin lymphoma ( 39 ), myeloma ( 40 ), renal carcinoma ( 41 ), and ovarian cancer ( 42 ). Therefore, TNFR2 is considered as an oncogene and targeting of TNFR2 with antagonistic antibodies as a novel strategy in cancer immunotherapy have been studied recently.…”
Section: Tnfr2 Antagonists Inhibit the Suppressive Activity Of Tregsmentioning
There is now compelling evidence that TNF receptor type II (TNFR2) is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF–TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation.
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