Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1487-1493 ◽  
Author(s):  
Martin Kleinhans ◽  
Adrian Tun-Kyi ◽  
Michel Gilliet ◽  
Marshall E. Kadin ◽  
Reinhard Dummer ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Actin Polymerization ◽  
Cell Lymphoma ◽  
Cell Suspensions ◽  
T Cell Lymphoma ◽  
Interleukin 4 ◽  
Cutaneous T Cell Lymphoma ◽  
Tissue Samples

Little is known about mechanisms involved in skin-specific homing of cutaneous T-cell lymphoma (CTCL). Chemokine/chemokine receptor interactions have been implicated in the homing of lymphoma cells to various tissue sites. We investigated tissue samples and tumor cell suspensions of patients with CD30+ CTCL (n = 8) and CD30− CTCL (mycosis fungoides, n = 6; Sézary syndrome, n = 6) for expression of the chemokine receptors CCR3, CCR4, and CCR8 and the CCR3 ligands eotaxin/CCL11, monocyte chemoattractant protein 3 (MCP-3)/CCL7, and RANTES (regulated on activation, normal T expressed and secreted)/CCL5. Of 8 CD30+ CTCLs, 7 expressed CCR3, 4 CCR4, and none CCR8. CCR3 expression was not found in skin tissue samples from 12 CD30− CTCLs. Coexpression of CCR3 and CD30 was demonstrated by flow cytometry in tumor cell suspensions. Internalization experiments demonstrated functionality of CCR3 expressed by freshly isolated tumor cells. Actin polymerization as well as migration in response to eotaxin was demonstrated in a CD30+ cutaneous lymphoma cell line. CCR3 ligand eotaxin/CCL11 was detected in lesional skin of CD30+CTCL by immunohistochemistry, preferentially in tumor cells. Eotaxin/CCL11 expression in tumor cells was confirmed by intracellular immunofluorescence. Analysis of cytokine expression pattern of CCR3-bearing infiltrating cells showed a predominance of interleukin-4 (IL-4) but not interferon-γ (IFN-γ) protein expression,1 consistent with a T-helper 2 (Th-2) profile. These results suggest that expression of CCR3 and its ligand eotaxin/CCL11 plays a role in the recruitment and retention of CD30+ malignant T cells to the skin.

scholarly journals Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

2020 ◽  
Author(s):  
Darci Phillips ◽  
Magdalena Matusiak ◽  
Belén Rivero Gutierrez ◽  
Salil S. Bhate ◽  
Graham L. Barlow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Tumor Cells ◽  
Spatial Organization ◽  
Cell Lymphoma ◽  
Post Treatment ◽  
T Cell Lymphoma ◽  
T Cell Subsets ◽  
Cutaneous T Cell Lymphoma

Anti-PD-1 immunotherapies have transformed cancer treatment, yet the determinants of clinical response are largely unknown. We performed CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced cutaneous T cell lymphoma (CTCL) patients enrolled in a clinical trial of pembrolizumab therapy. Clinical response was not associated with the frequency of tumor-infiltrating T cell subsets, but rather with striking differences in the spatial organization and functional immune state of the tumor microenvironment (TME). After treatment, pembrolizumab responders had a localized enrichment of tumor and CD4+ T cells, which coincided with immune activation and cytotoxic PD-1+ CD4+ T cells. In contrast, non-responders had a localized enrichment of Tregs pre- and post-treatment, consistent with a persistently immunosuppressed TME and exhausted PD-1+ CD4+ T cells. Integrating these findings by computing the physical distances between PD-1+ CD4+ T cells, tumor cells, and Tregs revealed a spatial biomarker predictive of pembrolizumab response. Finally, the chemokine CXCL13 was upregulated in tumor cells in responders post-treatment, suggesting that chemoattraction of PD-1+ CD4+ T cells towards tumor cells facilitates a positive outcome. Together, these data show that T cell topography reflects the balance of effector and suppressive activity within the TME and predicts clinical response to PD-1 blockade in CTCL.

scholarly journals Increased Soluble CD226 in Sera of Patients with Cutaneous T-Cell Lymphoma Mediates Cytotoxic Activity against Tumor Cells via CD155

2017 ◽  
Vol 137 (8) ◽  
pp. 1766-1773 ◽  
Author(s):  
Naomi Takahashi ◽  
Makoto Sugaya ◽  
Hiraku Suga ◽  
Tomonori Oka ◽  
Makiko Kawaguchi ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic Activity ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma

scholarly journals Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

2021 ◽  
Author(s):  
Garry Nolan ◽  
Darci Phillips ◽  
Magdalena Matusiak ◽  
Belén Gutierrez ◽  
Salil Bhate ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Tumor Cells ◽  
Cd4 T Cells ◽  
Cell Lymphoma ◽  
Post Treatment ◽  
T Cell Lymphoma ◽  
T Cell Subsets ◽  
Cutaneous T Cell Lymphoma

Abstract Anti-PD-1 immunotherapies have transformed cancer treatment, yet the determinants of clinical response are largely unknown. We performed CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced cutaneous T cell lymphoma (CTCL) patients enrolled in a clinical trial of pembrolizumab therapy. Clinical response was not associated with the frequency of tumor-infiltrating T cell subsets, but rather with striking differences in the spatial organization and functional immune state of the tumor microenvironment (TME). After treatment, pembrolizumab responders had a localized enrichment of tumor and CD4+ T cells, which coincided with immune activation and cytotoxic PD-1+ CD4+ T cells. In contrast, non-responders had a localized enrichment of Tregs pre- and post-treatment, consistent with a persistently immunosuppressed TME and exhausted PD-1+ CD4+ T cells. Integrating these findings by computing the physical distances between PD-1+ CD4+ T cells, tumor cells, and Tregs revealed a spatial biomarker predictive of pembrolizumab response. Finally, the chemokine CXCL13 was upregulated in tumor cells in responders post-treatment, suggesting that chemoattraction of PD-1+ CD4+ T cells towards tumor cells facilitates a positive outcome. Together, these data show that T cell topography reflects the balance of effector and suppressive activity within the TME and predicts clinical response to PD-1 blockade in CTCL.

Isolation of Tumor-Specific Cytotoxic CD4+ and CD4+CD8dim+ T-Cell Clones Infiltrating a Cutaneous T-Cell Lymphoma

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4331-4341 ◽  
Author(s):  
Martine Bagot ◽  
Hamid Echchakir ◽  
Fathia Mami-Chouaib ◽  
Marie-Hélène Delfau-Larue ◽  
Dominique Charue ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Autologous Tumor ◽  
Cutaneous T Cell Lymphoma ◽  
T Cell Clones ◽  
Cell Clones

We have isolated several T-cell clones from lymphocytes infiltrating a human major histocompatibility class (MHC) II negative cutaneous T-cell lymphoma (CTCL). We describe here two of these clones, TC5 and TC7, with, respectively, a CD4+CD8dim+ and CD4+CD8− phenotype. Both clones mediated a specific MHC class I–restricted cytotoxic activity toward the fresh autologous tumor cells, and autologous tumor cell lines previously established with interleukin-2 (IL-2) and IL-7 from the skin and from the blood. Analysis of the T-cell receptor (TCR) Vβ gene expression showed that the tumor cells, which were shown to have a trisomy 7 by fluorescent in situ hybridization, expressed Vβ7/Jβ2.3, Vβ13/Jβ2.5, and Vβ22/Jβ2.5 rearrangements. Phenotypic analysis using specific anti-Vβ monoclonal antibodies indicated that only Vβ13 could be detected on the cell membrane of the tumor cells. Analysis of the TCR Vβ gene expression of the clones showed that TC5 and TC7 expressed a unique TCR-Vβ transcript, corresponding, respectively, to Vβ5/Jβ2.3 and Vβ17/Jβ2.7 gene segments. To determine whether these reactive T lymphocytes were present in vivo, we used specific primers corresponding to TC5- and TC7-Vβ TCR transcripts. The results showed that both cytotoxic T-cell clones were present at the lesional skin site and amplified in vitro. TC7 was found in the patient peripheral blood invaded by tumoral cells, whereas TC5 was not, indicating that the repertoire of the reactional lymphocytes differs in the blood and at the tumor site. These results show for the first time the presence of reactive T lymphocytes with CD4 or double-positive phenotype infiltrating a CTCL. These findings raise the question of the role of these antitumoral effector T cells in the tumor growth.

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

2021 ◽  
Vol 22 (15) ◽  
pp. 7889
Author(s):  
Minami Sakamoto ◽  
Tomomitsu Miyagaki ◽  
Hiroaki Kamijo ◽  
Tomonori Oka ◽  
Hikari Boki ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Cyclophilin A ◽  
T Cell Lymphoma ◽  
Immunoglobulin Superfamily ◽  
Clinical Samples ◽  
Epidermal Keratinocytes ◽  
Cutaneous T Cell Lymphoma

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.

Down-regulating constitutive activation of the NF-κB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2354-2363 ◽  
Author(s):  
Aurore Sors ◽  
Francette Jean-Louis ◽  
Claire Pellet ◽  
Liliane Laroche ◽  
Louis Dubertret ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
High Ratio ◽  
T Cell Lymphoma ◽  
Luciferase Reporter ◽  
Cutaneous T Cell Lymphoma ◽  
Mobility Shift ◽  
Constitutive Activation

AbstractConstitutive activation of the nuclear factor-kappaB (NF-κB) pathway has been shown to be involved in the resistance of tumor cells to apoptosis in several human malignancies of the hematopoietic lineage. By using electrophoretic mobility shift assay (EMSA) and confocal microscopic analysis, we demonstrate that NF-κB is constitutively activated in cutaneous T-cell lymphoma (CTCL) cell lines HuT-78, MyLa, and SeAx and in peripheral blood lymphocytes (PBLs) from patients with Sézary syndrome (SS) presenting a high ratio of tumor cells, with evidence of p50 and RelA/p65 in DNA-linked complexes. Transfection of SeAx line with a κB/luciferase reporter plasmid showed that translocated NF-κB complexes were functional. Selective inhibition of NF-κB, by transfecting CTCL cell lines with a super-repressor form of IκBα, led to apoptosis. We evidenced down-regulation of NF-κB activation and induction of CTCL cell apoptosis in the presence of proteasome 26S inhibitors ALLN, MG132, and bortezomib. Bortezomib at nanomolar concentrations inhibited constitutive activation of NF-κB and induced apoptosis of CTCL cells, with evidence of an upregulation of Bax expression. These results demonstrate the key role played by NF-κB in the resistance of CTCL to apoptosis and suggest that bortezomib might be useful for the treatment of patients with advanced stages of CTCL refractory to standard antineoplastic chemotherapy.

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