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Chemokines and Chemokine Receptor Interactions and Functions
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Philip L. Shields, David H. Adams
CCR5 (the receptor for MIP-1α, MIP-1β and RANTES)and CXCR3 (the receptor for IP-10, Mig and I-TAC) show increased expression on human peripheral blood memory CD45RO+ T cells (50). CCR5 and CXCR4 appear to denote an effector phenotype as these cells are predominantly CCR7 negative (49). Tissue infiltrating T cells in rheumatoid synovium which are predominantly of a memory phenotype have also been shown to express high levels of CXCR3 and CCR5 (51). CCR4 marks memory T cells, but its expression appears to be even more specific; skin homing memory T cells express high levels of this receptor, whereas gut homing memory T cells express low levels. CCR4 may, therefore, direct tissue specific T cell migration (48).
Targeting Human T-Cell Leukemia Virus Type 1
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
An alternative approach to ATL therapy is to target cell-surface markers on the malignant cells with monoclonal antibodies. CC chemokine receptor 4 (CCR4) is expressed on leukemic cells from most ATL cases (Yoshie et al. 2002; Ishida et al. 2003). A humanized anti-CCR4 monoclonal antibody, mogamulizumab, with a defucosylated Fc region was developed and proved to markedly enhance antibody- dependent cellular cytotoxicity in ATL cells (Ishida et al. 2012). A clinical trial of mogamulizumab demonstrated significant response in relapsed ATL patients. Now, mogamulizumab is available in Japan as one of the treatment options for refractory ATL. An anti-CD25 (anti-Tac) monoclonal antibody was first administered to ATL patients in the late 1980s (Waldmann et al. 1988) and was reported to be effective in some patients (CR, 2/19; PR, 4/19) (Waldmann et al. 1993). It was reported that the anti-CD52 monoclonal antibody Campath-1H was effective in one patient with AZT/IFN-α-refractory ATL (Mone et al. 2005). A humanized anti-CD2 antibody (MEDI-507) has also been shown to be effective in a xenograft mouse model (Zhang et al. 2003).
Human T-Lymphotropic Virus
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Anti-CC chemokine receptor 4 (CCR4) antibodies, which is another humanized antibody, might also be considered for use in the treatment of HAM/TSP in future. Anti-CCR4 antibody has a strong antibody-dependent cellular cytotoxic effect, and favorable results in a phase I study of anti-CCR4 antibody focused on the treatment of relapsed CCR4-positive ATL and peripheral T-cell lymphoma have been presented (Yamamoto et al. 2010).
Metformin combats obesity by targeting FTO in an m6A-YTHDF2-dependent manner
Published in Journal of Drug Targeting, 2022
Xing Liao, Jiaqi Liu, Yushi Chen, Youhua Liu, Wei Chen, Botao Zeng, Yuxi Liu, Yaojun Luo, Chaoqun Huang, Guanqun Guo, Yizhen Wang, Xinxia Wang
m6A binding proteins, also termed m6A readers, are up to date classified mainly by YT521-B homology (TYH) protein family, heterogenous nuclear ribonucleoproteins (HNRNP) protein family as well as insulin-like growth factor 2 mRNA binding protein (IGF2BP) protein family, and have been reported to play essential roles in translation, decay, stabilisation, splicing and export of RNAs by preferentially binding m6A-modified RNAs [37]. As a member of TYH protein family, YTHDF2 was identified to accelerate degradation of m6A-modified RNAs by recruiting the CCR4-NOT deadenylase complex [45]. Consistent with what was proven previously, our study showed that YTHDF2 could shorten mRNA lifetime of Ccnd1 and Cdk2, whereas depletion of Ythdf2 reversed the suppressed expression level of MCE-related proteins, suggesting that the negative correlation of m6A modification and expression levels of Ccnd1 and Cdk2 occurred in an m6A-YTHDF2-dependent manner.
Contemporary strategies to improve outcomes for peripheral T-cell lymphoma patients following the failure of first-line therapy
Published in Expert Review of Hematology, 2020
Avyakta Kallam, James O. Armitage
Mogamulizumab is a monoclonal antibody directed against C-C motif chemokine receptor 4(CCR4). CCR4 is a seven transmembrane receptor that is expressed on regulatory T cells (T regs). Cells that overexpress CCR4 impair host anti-tumor activity. Mogamulizumab depletes CCR4 positive Treg, resulting in an anti-tumor immune response. A phase II study of mogamulizumab was conducted in patients with relapsed CCR4 positive PTCL or CTCL [46]. The ORR for 37 evaluable patients was 35%, with a CR noted in 5 patients. The median OS was not reached at a median follow up of 14.2 months. The most common adverse events were infusion reactions, rash, and hematological toxicities. This study led to the approval of the study in Japan. A similar phase II European study by Zinzani et.al. evaluating mogamulizumab in relapsed/refractory CCR4-positive PTCL showed a lower ORR of 11% [47]. This difference was thought to be due to inclusion of refractory and relapsed patients in the study, whereas Ogura et.al included patients with the relapsed disease only. Due to the lack of substantial efficacy in PTCL, mogamulizumab is FDA approved in the US for use in patients with CTCL only. Studies are ongoing evaluating its role in combination therapies in PTCL.
Emerging therapeutic targets for nasopharyngeal carcinoma: opportunities and challenges
Published in Expert Opinion on Therapeutic Targets, 2020
Valentin Baloche, François-Régis Ferrand, Anna Makowska, Caroline Even, Udo Kontny, Pierre Busson
In the section about NPC tumor microenvironment, we have mentioned several biomolecules released by malignant cells which are suspected to contribute to the local immunosuppression, including LIF, CCL20 and galectin-9. Antibodies neutralizing LIF are currently in clinical development for human malignancies but, to our knowledge, have not been specifically tested in NPC patients [115](NCT03490669). The development of antibodies neutralizing CCL20 is much less advanced [116]. Therapeutic antibodies neutralizing extra-cellular galectin-9 are currently under pre-clinical development [117]. CCR4 is a chemokine receptor expressed at the surface of T-regs which mediates the chemotactic effect of CCL17 and CCL22. Both cytokines are abundant in some EBV-related malignancies like NK/T cell lymphomas [118]. It would be interesting to know their status in NPCs. Small molecules blocking CCR4 are currently in pre-clinical development (American Association for Cancer Research meeting, 2018, abstract #4752).