Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma

Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma

Electrospray ionization mass spectrometric characterization of key Te(IV) cationic intermediates for the addition of TeCl4 to alkynes

Leonardo Silva Santos. Universidad de Talca, Instituto de Química de Recursos Naturales, P.O. Box 747, Talca, Chile.Tellurium tetrachloride adds to alkynes via two pathways: a concerted syn-addition that yields Z-tri- and -tetrasubstituted alkenes or an anti-addition that yields E-alkenes. The mechanistic aspects of these divergent pathways for TeCl4 addition to alkynes have been investigated by on-line electrospray ionization (tandem) mass spectrometry (ESI-MS(/MS)). Via ESI-MS(/MS), we have been able to intercept and characterize the active electrophile TeCl in tetrahydrofuran (THF) solutions of TeCl4, as well as its THF complex and several TeClx(OH) derivatives. For the first time, also, key Te(IV) cationic intermediates of the electrophilic addition of TeCl4 to alkynes were captured for gas-phase MS investigation. The detailed structural data of cyclic tellurane intermediates intercepted herein seems to provide insights into the coordinative behavior of the Te(IV) atom and its mode of action towards biological targets. Copyright © 2007 John Wiley & Sons, Ltd

Electrospray ionization mass spectrometric characterization of key Te(IV) cationic intermediates for the addition of TeCl4 to alkynes

Tellurium tetrachloride adds to alkynes via two pathways: a concerted syn-addition that yields Z-tri- and -tetrasubstituted alkenes or an anti-addition that yields E-alkenes. The mechanistic aspects of these divergent pathways for TeCl4 addition to alkynes have been investigated by on-line electrospray ionization (tandem) mass spectrometry (ESI-MS(/MS)). Via ESI-MS(/MS), we have been able to intercept and characterize the active electrophile TeCl3+ in tetrahydrofuran (THF) solutions of TeCl4, as well as its THF complex and several TeClx(OH)(y)(+) derivatives. For the first time, also, key Te(IV) cationic intermediates of the electrophilic addition of TeCl4 to alkynes were captured for gas-phase MS investigation. The detailed structural data of cyclic tellurane intermediates intercepted herein seems to provide insights into the coordinative behavior of the Te(IV) atom and its mode of action towards biological targets. Copyright (c) 2007 John Wiley & Sons, Ltd.2191479148

Suzuki-Miyaura cross-coupling reactions of aryl tellurides with potassium aryltrifluoroborate salts

Palladium(O)-catalyzed cross-coupling between potassium aryltrifluoroborate salts and aryl tellurides proceeds readily to afford the desired biaryls in good to excellent yield. the reaction seems to be unaffected by the presence of electron-withdrawing or electron-donating substituents in both the potassium aryltrifluoroborate salts and aryl tellurides partners. Biaryls containing a variety of functional groups can be prepared. A chemoselectivity study was also carried out using aryl tellurides bearing halogen atoms in the same compound. in addition, this new version of the Suzuki-Miyaura cross-coupling reaction was monitored by electrospray ionization mass spectrometry where some reaction intermediates were detected and analyzed.Univ São Paulo, Inst Quim, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biofis, São Paulo, BrazilUniv São Paulo, Fac Ciencias Farmaceut, São Paulo, BrazilInst Butantan, CEPID, CAT, Lab Espectrometria Massas, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biofis, São Paulo, BrazilWeb of Scienc