Down-Modulation of CXCR3 Surface Expression and Function in CD8+ T Cells from Cutaneous T Cell Lymphoma Patients

Winter, Dorian; Moser, Julia; Kriehuber, Ernst; Wiesner, Christoph; Trautinger, Franz; Bombosi, Paula; Stingl, Georg; Petzelbauer, Peter; Rot, Antal; Maurer, Dieter

doi:10.4049/jimmunol.179.6.4272

Cited by 16 publications

(10 citation statements)

References 35 publications

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“…Although these chemokines are known to attract T cells to sites of inflammation, they are also known to be highly expressed during melanoma and other cancer burdens, allowing malignant cancer cells to migrate to distant nodes (45, 62). CXCR3 + T cells in the presence of these high chemokines also can lose CXCR3 expression preventing the cells from migrating into the cancerous tissue (63). In fact, we see high levels of these chemokines during recurrence and loss of CXCR3 on the tumor-specific CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Restoring Immune Function of Tumor-Specific CD4+ T Cells during Recurrence of Melanoma

Goding

Wilson

Xie

et al. 2013

The Journal of Immunology

182

159

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Recurrent solid malignancies are often refractory to standard therapies. While adoptive T cell transfer may benefit select individuals, the majority of patients succumb to their disease. In order to address this important clinical dilemma, we developed a mouse melanoma model in which initial regression of advanced disease was followed by tumor recurrence. During recurrence, Foxp3+ tumor-specific CD4+ T cells became PD-1+ and represented over 60% of the tumor-specific CD4+ T cells in the host. Concomitantly, tumor-specific CD4+ T effector cells showed traits of chronic exhaustion as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. While blockade of the PD-1/PD-L1 pathway with anti-PD-L1 antibodies or depletion of tumor-specific Treg cells alone failed to reverse tumor recurrence, combination of PD-L1 blockade with tumor-specific Treg cell depletion effectively mediated disease regression. Furthermore, blockade with a combination of anti-PD-L1 and anti-LAG-3 antibodies overcame the requirement to deplete tumor-specific Treg cells. In contrast, successful treatment of primary melanoma with adoptive cell therapy required only Treg depletion or antibody therapy, underscoring the differences in the characteristics of treatment between primary and relapsing cancer. These data highlight the need for preclinical development of combined immunotherapy approaches specifically targeting recurrent disease.

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Section: Discussionmentioning

confidence: 99%

Restoring Immune Function of Tumor-Specific CD4+ T Cells during Recurrence of Melanoma

Goding

Wilson

Xie

et al. 2013

The Journal of Immunology

182

159

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“…It has been reported that CXCR3 is downregulated in several pathological conditions, in which serum sHLA-G levels are increased, such as allergy[45], T cell lymphoma[46]and multiple sclerosis [47]. Conversely, CXCR3 has been found to be upregulated in diseased associated with decerased levels of serum sHLA-G, such as rheumatoid arthritis and lupus [48].…”

Section: Discussionmentioning

confidence: 99%

A Novel Mechanism of Soluble HLA-G Mediated Immune Modulation: Downregulation of T Cell Chemokine Receptor Expression and Impairment of Chemotaxis

et al. 2010

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BackgroundIn recent years, many immunoregulatory functions have been ascribed to soluble HLA-G (sHLA-G). Since chemotaxis is crucial for an efficient immune response, we have investigated for the first time the effects of sHLA-G on chemokine receptor expression and function in different human T cell populations.Methodology/Principal FindingsT cell populations isolated from peripheral blood were stimulated in the presence or absence of sHLA-G. Chemokine receptors expression was evaluated by flow cytometry. sHLA-G downregulated expression of i) CCR2, CXCR3 and CXCR5 in CD4+ T cells, ii) CXCR3 in CD8+ T cells, iii) CXCR3 in Th1 clones iv) CXCR3 in TCR Vδ2γ9 T cells, and upregulated CXCR4 expression in TCR Vδ2γ9 T cells. sHLA-G inhibited in vitro chemotaxis of i) CD4+ T cells towards CCL2, CCL8, CXCL10 and CXCL11, ii) CD8+ T cells towards CXCL10 and CXCL11, iii) Th1 clones towards CXCL10, and iv) TCR Vδ2γ9 T cells towards CXCL10 and CXCL11. Downregulation of CXCR3 expression on CD4+ T cells by sHLA-G was partially reverted by adding a blocking antibody against ILT2/CD85j, a receptor for sHLA-G, suggesting that sHLA-G downregulated chemokine receptor expression mainly through the interaction with ILT2/CD85j. Follicular helper T cells (TFH) were isolated from human tonsils and stimulated as described above. sHLA-G impaired CXCR5 expression in TFH and chemotaxis of the latter cells towards CXCL13. Moreover, sHLA-G expression was detected in tonsils by immunohistochemistry, suggesting a role of sHLA-G in local control of TFH cell chemotaxis. Intracellular pathways were investigated by Western Blot analysis on total extracts from CD4+ T cells. Phosphorylation of Stat5, p70 s6k, β-arrestin and SHP2 was modulated by sHLA-G treatment.Conclusions/SignificanceOur data demonstrated that sHLA-G impairs expression and functionality of different chemokine receptors in T cells. These findings delineate a novel mechanism whereby sHLA-G modulates T cell recruitment in physiological and pathological conditions.

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“…The importance of T-cell-expressed CXCR3 is illustrated by the observation that patients with cutaneous T-cell lymphomas had decreased surface expression of CXCR3 on circulating CD8 + T cells [39]. Although CXCR3 transcript levels were normal, surface receptor expression was diminished, and, not surprisingly, these cells migrated poorly to CXCR3 ligands.…”

Section: Cxcr3 Ligandsmentioning

confidence: 98%

The chemokine receptors CXCR4 and CXCR3 in cancer

Fulton

2009

Curr Oncol Rep

106

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Chemokines comprise a superfamily of at least 46 cytokines that were initially described based on their ability to bind to 18 to 22 G protein-coupled receptors to induce the directed migration of leukocytes to sites of inflammation or injury. In addition to mediating cellular migration, chemokine/chemokine receptor pairs have been shown to affect many cellular functions, including survival, adhesion, invasion, and proliferation, and to regulate circulating chemokine levels. Most malignancies also express one or more chemokine receptors. Early studies established a role for CXCR4 and CXCR7 in mediating breast cancer metastasis, but other chemokine receptors, including CXCR3, now are implicated in several malignancies as biomarkers of tumor behavior as well as potential therapeutic targets. This review summarizes our current understanding regarding the contribution of CXCR4 and CXCR3 to tumor behavior and how receptor expression is regulated, transduces intracellular signals, and contributes at the molecular level to tumor behavior. It also describes recent therapeutic approaches that target these receptors or their ligands.

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Down-Modulation of CXCR3 Surface Expression and Function in CD8+ T Cells from Cutaneous T Cell Lymphoma Patients

Cited by 16 publications

References 35 publications

Restoring Immune Function of Tumor-Specific CD4+ T Cells during Recurrence of Melanoma

Restoring Immune Function of Tumor-Specific CD4+ T Cells during Recurrence of Melanoma

A Novel Mechanism of Soluble HLA-G Mediated Immune Modulation: Downregulation of T Cell Chemokine Receptor Expression and Impairment of Chemotaxis

The chemokine receptors CXCR4 and CXCR3 in cancer

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