CCR4 in cutaneous T‐cell lymphoma: Therapeutic targeting of a pathogenic driver

Nicolay, Jan P.; Albrecht, Julia N.; Alberti‐Violetti, Silvia; Berti, Emilio

doi:10.1002/eji.202049043

Cited by 39 publications

(23 citation statements)

References 71 publications

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“…Sézary syndrome (SS) is the representative aggressive CTCL and is characterized by the triad of generalized erythroderma, lymphadenopathy, and leukemic involvement [1,2]. MF and SS share common features, such as epidermotropism of tumor cells and CD4, CD45RO, and CCR4 expression in tumor cells [1,3]. Patients with advanced MF and SS have poor prognosis, with 5-year survival rates of 52% and median overall survival of 63 months [4].…”

Section: Introductionmentioning

confidence: 99%

CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma

Sakamoto

Miyagaki

Kamijo

et al. 2021

IJMS

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CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.

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Section: Introductionmentioning

confidence: 99%

CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma

Sakamoto

Miyagaki

Kamijo

et al. 2021

IJMS

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“…The chemokine receptors, such as cutaneous lymphocyte-associated antigen [ 5 ], CCR4 [ 38 ], CCR8 [ 39 ], CCR10 [ 40 ], CXCR3 [ 26 , 37 ], and CXCR6 [ 41 ] have also been reported to play important roles in homing and/or retention in skin. The contribution of some of these molecules to MF pathogenesis and prognosis has been demonstrated [ 7 , 42 , 43 ], supporting the skin-tropic phenotype of malignant T cells in MF and the involvement of the tumor microenvironment in disease manifestation, as described in Section 7 . However, although the malignant T cells in CTCL are in most cases CD4 T cells, the information on the development of CD4 T RM is still limited.…”

Section: The Development Of Skin T Rmmentioning

confidence: 65%

Malignant and Benign T Cells Constituting Cutaneous T-Cell Lymphoma

Nakai

Kiyohara

Watanabe

2021

IJMS

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Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma, including various clinical manifestations, such as mycosis fungoides (MF) and Sézary syndrome (SS). CTCL mostly develops from CD4 T cells with the skin-tropic memory phenotype. Malignant T cells in MF lesions show the phenotype of skin resident memory T cells (TRM), which reside in the peripheral tissues for long periods and do not recirculate. On the other hand, malignant T cells in SS represent the phenotype of central memory T cells (TCM), which are characterized by recirculation to and from the blood and lymphoid tissues. The kinetics and the functional characteristics of malignant cells in CTCL are still unclear due, in part, to the fact that both the malignant cells and the T cells exerting anti-tumor activity possess the same characteristics as T cells. Capturing the features of both the malignant and the benign T cells is necessary for understanding the pathogenesis of CTCL and would lead to new therapeutic strategies specifically targeting the skin malignant T cells or benign T cells.

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“…Mogamulizumab, a non-fucosylated, humanized antibody specific for human CCR4, is another recent example of an approved antibody reagent causing irAEs in patients with cancer [128,129]. The ADCC-active antibody reagent is approved in the USA and Europe for the treatment of cutaneous T cell lymphomas, including patients suffering from advanced forms of mycosis fungoides or Sezary syndrome, as well as in Japan for advanced adult and peripheral T cell lymphoma [130][131][132]. The distribution of CCR4 + cells is relatively widespread and includes platelets, NK cells, mast cells and T cells [4].…”

Section: Safety Concerns Related To Ccr8-targeted Therapiesmentioning

confidence: 99%

Chemokine Receptor-Targeted Therapies: Special Case for CCR8

Moser

2022

Cancers

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Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Recent reports revealed the selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. In this review, I summarize our current knowledge about the cellular distribution and function of CCR8 in physiological and pathophysiological processes. The discussion includes an assessment of how the removal of CCR8-expressing cells might affect both anti-tumor immunity as well as immune homeostasis at remote sites. Based on these considerations, CCR8 appears to be a promising novel target to be considered in future translational research.

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CCR4 in cutaneous T‐cell lymphoma: Therapeutic targeting of a pathogenic driver

Cited by 39 publications

References 71 publications

CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma

CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma

Malignant and Benign T Cells Constituting Cutaneous T-Cell Lymphoma

Chemokine Receptor-Targeted Therapies: Special Case for CCR8

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