scholarly journals NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression

2021 ◽  
Vol 12 ◽  
Author(s):  
Enrique Huanosta-Murillo ◽  
Marcela Alcántara-Hernández ◽  
Brenda Hernández-Rico ◽  
Georgina Victoria-Acosta ◽  
Patricia Miranda-Cruz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Skin Lesions ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Th2 Response ◽  
Potentially Malignant

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.

scholarly journals High IKZF2 Expression in Malignant T cells Promotes Disease Progression in Cutaneous T cell Lymphoma

2021 ◽  
Author(s):  
Bufang Xu ◽  
Fengjie Liu ◽  
Yumei Gao ◽  
Jingru Sun ◽  
Yingyi Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Malignant Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Tumor Immune Escape ◽  
Malignant T Cells

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, CTCL may manifest as aggressive clinical behavior and lead to a poor prognosis. The mechanism of disease progression in CTCL remains unknown. Here, with a large clinical cohort, we identified that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage-dependent overexpression in the malignant T cells in MF lesions. IKZF2 is specifically over-expressed in advanced-stage MF lesions, correlates with poor patient prognosis. Mechanistically, IKZF2 overexpression promotes CTCL progression via inhibiting malignant cell apoptosis and may contribute to tumor immune escape by downregulating MHC-II molecules and up-regulating the production of anti-inflammatory cytokine IL-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk CTCL and pave the way for future targeted therapy.

scholarly journals High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1966-1976 ◽  
Author(s):  
Rachael A. Clark ◽  
Jeffrey B. Shackelton ◽  
Rei Watanabe ◽  
Adam Calarese ◽  
Kei-ichi Yamanaka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Skin Diseases ◽  
Cell Lymphoma ◽  
Early Stage ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Skin ◽  
Malignant T Cells

Abstract In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (THS) cells were CD4+ in CD4+ mycosis fungoides (MF), CD8+ in CD8+ MF, and contained only clonal T cells in patients with identifiable malignant Vβ clones. THS cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal THS cells correlated with skin disease in patients followed longitudinally. Clonal THS cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

scholarly journals Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Katharina Rindler ◽  
Constanze Jonak ◽  
Natalia Alkon ◽  
Felix M. Thaler ◽  
Harald Kurz ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Disease Progression ◽  
Rna Sequencing ◽  
Cell Lymphoma ◽  
Early Stage ◽  
T Cell Lymphoma ◽  
Advanced Stage ◽  
Cutaneous T Cell Lymphoma ◽  
Single Cell Rna Sequencing

Abstract Background In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20–30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. Methods In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin. Results Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69, the heat shock protein HSPA1A, the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP, and the interleukin 7 receptor (IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers. Conclusions Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

scholarly journals Ectopic expression of a novel CD22 splice-variant regulates survival and proliferation in malignant T cells from cutaneous T cell lymphoma (CTCL) patients

Oncotarget ◽  
2015 ◽  
Vol 6 (16) ◽  
pp. 14374-14384 ◽  
Author(s):  
Ieva Bagdonaite ◽  
Hans H. Wandall ◽  
Ivan V. Litvinov ◽  
Claudia Nastasi ◽  
Jürgen C. Becker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Splice Variant ◽  
Cell Lymphoma ◽  
Ectopic Expression ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Malignant T Cells

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.

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