Targeting Human T-Cell Leukemia Virus Type 1
Satya Prakash Gupta in 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).
The Role of Human Genetics in HIV-1 Infection
Thomas R. O’Brien in Chemokine Receptors and AIDS, 2019
The CCR5 gene has been mapped to the short arm of chromosome 3 within a chemokine receptor gene cluster that includes CCR1, CCR2, CCR3, CCR4, CCR6, CCR8, and CX3CR1 (58–60). The CCR5 gene became an obvious disease gene candidate for HIV-1 infection upon the discovery of CCR5 as a co-receptor for HIV-1 and screening the coding region of the gene was easily performed since it contains a single open reading frame (exon 4) of only 1,055 base pairs. A common, severe mutation characterized by a 32 base pair deletion, CCR5-Δ32, was rapidly identified (8–10). The deletion begins in the region encoding the third extracellular domain of CCR5, and results in a frame shift and premature stop codon in the fifth transmembrane domain. The truncated protein product is not expressed on the cell surface (9), explaining the nearly complete protection against HIV-1 infection (see Table 1), despite repeated exposures, in individuals homozygous for the mutant allele (8–10,61,62). Accordingly, peripheral blood lymphocytes (PBLs) from individuals homozygous for CCR5-Δ32 are resistant to infection with R5 (but not X4) strains of HIV-1 in vitro (9,10,63,64). The normal CCR5 function appears to be dispensable, perhaps because of the redundancy of the chemokine receptor system, since individuals who are homozygous for the CCR5-Δ32 are generally unremarkable (see Chapter 10).
Lymphocyte homing and immunology of extranodal lymphoid tissues
Franco Cavalli, Harald Stein, Emanuele Zucca in Extranodal Lymphomas, 2008
While all naive cells share the same repertoire of adhesion molecules and chemoattractant receptors expressed on their surfaces, various subsets of memory cells express different repertoires of such homing molecules. The homing properties of memory cells are dependent upon the repertoire of homing molecules that they express.2,8 For example, approximately 20% of memory Th2 lymphocytes from human peripheral blood express the cutaneous lymphocyte antigen (CLA). CLA is a carbohydrate that allows lymphocytes to roll on E-selectin-expressing blood vessels. A separate ~20% of memory Th2 lymphocytes from blood express the α4β7-integrin (Figure 5.1).2,8 As discussed in the previous section, α4β7 allows rolling and adhesion within vessels expressing the mucosal addressin MAdCAM-1.14–16 There are essentially no Th2 cells that express both CLA and α4β7 together, so these markers define distinct populations. Similar contrasts are found for expression of chemokine receptors: CCR4 is found primarily on α4β7-negative Th2 cells,34–36 whereas CCR9 is found only on a subset of α4β7-positive Th2 cells.37 To complete the picture, cutaneous and intestinal tissues have differential expression of the ligands for these chemokine receptors and homing molecules.34,38 Study of lymphocytes isolated from surgical samples of such tissues confirm that co-expression of CLA and CCR4 defines the population of memory Th2 lymphocytes that is specialized to home through cutaneous sites.34–36 CCR10 is also expressed on a subset of cutaneous lymphocytes, and may also play a role in cutaneous homing.39 Co-expression of α4β7 and CCR9 defines a population of memory Th2 cells dedicated to homing to the small intestine.37,38,40
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).
MiRNA-6089 inhibits rheumatoid arthritis fibroblast-like synoviocytes proliferation and induces apoptosis by targeting CCR4
Published in Archives of Physiology and Biochemistry, 2022
Suxian Lin, Shengnan Wang, Zhiyong Zhang, Yang Lu, Meilv Yang, Ping Chen, Lianguo Chen, Mudan Wang
Recently, several studies showed that CCR4 is highly expressed on circulating Tregs (Watanabe et al. 2019). Tregs is recruited at tumour sites in many cancers, such as breast cancer and colorectal cancer (Sasidharan Nair et al. 2020). The anti-CCR4 antibody, alone or in combination with other immune modulators may potentially be used in the treatment of a human solid cancer with high levels of CCR4 expression in tumour-infiltrating leukocytes and abnormal plasma CCR4 ligand levels (Berlato et al. 2017). Importantly, CCR4 has been widely implicated in the pathogenesis of inflammatory diseases such as asthma and atopic dermatitis due to its expression on Th2 cells (Anderson et al. 2020). In our study, we found an increased mRNA level of CCR4 in synovial tissues, and the overexpression CCR4 reversed the effects of miR-6089 on proliferation and apoptosis in RA-FLSs. Our results showed that miR-6089 performed its inhibitory role in the development of RA-FLSs, at least in part, by targeting CCR4.
CCL22-based peptide vaccines induce anti-cancer immunity by modulating tumor microenvironment
Published in OncoImmunology, 2022
Inés Lecoq, Katharina L. Kopp, Marion Chapellier, Panagiotis Mantas, Evelina Martinenaite, Maria Perez-Penco, Lars Rønn Olsen, Mai-Britt Zocca, Ayako Wakatsuki Pedersen, Mads Hald Andersen
The CCL22:CCR4 axis has been shown to function as an immune checkpoint; this axis is crucial for controlling T-cell immunity, particularly in the TME context, where a CCL22 deficiency was correlated with prolonged survival.43 Consequently, different approaches to disrupt this axis are currently under investigation. A CCR4 antagonist (mogamulizumab), was recently developed to disrupt CCL22:CCR4-mediated Treg recruitment to the tumor.44 Anti-CCR4 antibodies showed promising results in vivo. These antibodies effectively inhibited chemotactic Treg recruitment to the tumor in a CCL22-dependent manner, which led to the restoration of anti-tumor immunity in a humanized murine model.17 Furthermore, those findings were reproduced in a clinical setting, and in 2018, mogamulizumab was approved by the FDA for the treatment of cutaneous T-cell lymphoma. Subsequently, a phase Ia trial tested a combination therapy of mogalinumab and nivolumab (anti-PDL1) in multicancer solid tumors and found that effector Tregs were depleted in peripheral blood and in the TME.45 In some cases, the Treg depletion induced by mogamulizumab was associated with serious autoimmune side effects.46,47 Its application in combination with checkpoint inhibitors was tested in a phase I48 and a phaseI/II49 study. However, the combination did not results in a potent antitumor efficacy in patients with advanced solid tumors therefore, leaving an open door for other approaches aiming at targeting Treg recruitment through the CCL22:CCR4 axis.
Related Knowledge Centers
- Ccl17
- Ccl2
- Ccl22
- Ccl5
- Chemokine
- Cluster of Differentiation
- Protein
- White Blood Cell
- Gene
- Cluster of Differentiation
- G Protein-Coupled Receptor