Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug

Ramsay, Alan G.; Johnson, Amy J.; Lee, Abigail M.; Görgün, Güllü; Dieu, Rifca Le; Blum, William; Byrd, John C.; Gribben, John G.

doi:10.1172/jci35017

Cited by 392 publications

(590 citation statements)

References 45 publications

Supporting

Mentioning

542

Contrasting

Unclassified

Order By: Relevance

“…Using these samples, we clearly demonstrated that LN-CLL cells had enhanced expression of markers that would induce T-cell activation. In contrast to previous studies, which suggest that PB-CLL cells are poor APCs, 22,27 induce T-cell anergy, and inhibit T-cell activation, 20,21,28 we showed that LN-CLL cells can induce T-cell activation and proliferation. We also showed that, in contrast to PB-CLL cells, those from the LN were capable of forming immune synapses with autologous CD4 1 T cells that were comparable to those formed by healthy B and T cells.…”

Section: Discussioncontrasting

confidence: 99%

“…Previous work has shown that PB-CLL cells exhibit impaired T-cell synapse formation. 20 Here, we measured synapse assembly (CLL:CD4 1 T-cell conjugates) in 4 patient samples and demonstrated for the first time that LN-CLL cells showed enhanced autologous T-cell synapse formation, equivalent to that induced by healthy B cells, 24 BLOOD, 28 JULY 2016 x VOLUME 128, NUMBER 4…”

Section: Enhanced Capacity Of Ln-derived Cll Cells To Activate T Cellsmentioning

confidence: 88%

“…6,18 The objective of the present study was to reconcile these findings with the extensive previous evidence that CLL cells strongly inhibit T-cell activation. [19][20][21] Previous studies assessing the T-cell activation capabilities of CLL cells have used cells derived from the PB, which it has been suggested induces anergy. 22 However, these cells are known to have different properties to those residing within the LNs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

Pasikowska

Walsby

Apollonio

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• LN-derived CLL cells have increased capacity for T-cell activation and superior immune synapse formation compared with those from PB.• Enhanced CLL cell immunologic function is also linked to PB circulating cells with the propensity to migrate.Several lines of evidence suggest that homing of tumor cells to lymphoid tissue contributes to disease progression in chronic lymphocytic leukemia (CLL). Here, we demonstrate that lymph node (LN)-derived CLL cells possess a distinct phenotype, and exhibit enhanced capacity for T-cell activation and superior immune synapse formation when compared with paired peripheral blood (PB) samples. LN-derived CLL cells manifest a proliferative, CXCR4 dim CD5 bright phenotype compared with those in the PB and higher expression of T-cell activation molecules including CD80, CD86, and HLA-D-related (DR). In addition, LN-CLL cells have higher expression of a4b1 (CD49d) which, as well as being a co-stimulatory molecule, is required for CLL cells to undergo transendothelial migration (TEM) and enter the proliferation centers of the LNs. Using an in vitro system that models circulation and TEM, we showed that the small population of CLL cells that migrate are CXCR4 dim CD5 bright with higher CD49d, CD80, CD86, and HLA-DR compared with those that remain circulating; a phenotype strikingly similar to LN-derived CLL cells. Furthermore, sorted CD49d hi CLL cells showed an enhanced capacity to activate T cells compared with CD49d lo subpopulations from the same patient. Thus, although PB-CLL cells have a reduced capacity to form immune synapses and activate CD4 1 T cells, this was not the case for LN-CLL cells or those with the propensity to undergo TEM. Taken together, our study suggests that CLL cell immunologic function is not only modulated by microenvironmental interactions but is also a feature of a subpopulation of PB-CLL cells that are primed for lymphoid tissue homing and interaction with T cells. (Blood. 2016;128(4):563-573)

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Enhanced Capacity Of Ln-derived Cll Cells To Activate T Cellsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

Pasikowska

Walsby

Apollonio

et al. 2016

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…6 Indeed, T-cell abnormalities occurring alongside CLL have been observed for a long time 7,8 and, more recently, an aberrant interaction between T cells and CLL cells has been described. 9 Our own previous work suggested that in human CLL the T-cell subset composition is severely skewed and that this was associated with stage, progressive disease, and time to development of a treatment indication. 10 These data suggested that an accumulation of antigen-experienced T cells in the memory compartment were somehow associated with a more aggressive disease course.…”

Section: Introductionmentioning

confidence: 99%

Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL

et al. 2011

View full text Add to dashboard Cite

Chronic lymphocytic leukemia (CLL) cells require complex microenvironmental and immunologic interactions to survive and proliferate. Such interactions might be best recreated in animal models; however, this needs extensive verification. We therefore investigated the composition of the T-cell compartment in the El-TCL1 transgenic mouse, currently the most widely used murine model for CLL. Immunophenotyping and transplant approaches were used to define T-cell subsets at various stages of CLL. Analogous to human CLL, we observed a skewing of T-cell subsets from naive to antigen-experienced memory T cells that was more pronounced in lymph nodes than in blood. Transplantation of CLL into non-transgenic recipients was feasible without immunosuppression in a pure C57BL/6 background and resulted in the prominent skewing of the T cells of the recipient mice. Both in spontaneously developed CLL and in the transplantation setting, a loss in T-cell receptor diversity was observed, with a relevant number of clonal T-cell populations arising. This suggests that antigen-dependent differentiation toward the T memory pool is initiated by murine CLL cells. In summary, we validate the TCL1 transgenic mouse model for analysis of T-cell phenotypes and suggest a CLL-dependent antigen-driven skewing of T cells in these mice.

show abstract

“…The mechanisms whereby this occurs are poorly understood, but include direct cancer cell-T cell interactions, production of immune-suppressive factors by cancer cells, and induction of regulatory T-cell subsets (1,2). Understanding the elusive mechanisms of tumor-driven immune evasion will aid the refinement of existing cancer immunotherapy strategies and identify novel treatments.…”

mentioning

confidence: 99%

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Görgün¹,

Ramsay

Holderried³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

102

View full text Add to dashboard Cite

Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) E -TCL1 transgenic mouse model. With development of leukemia, E -TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young E -TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.C ancer cells induce changes in the tumor microenvironment.The mechanisms whereby this occurs are poorly understood, but include direct cancer cell-T cell interactions, production of immune-suppressive factors by cancer cells, and induction of regulatory T-cell subsets (1, 2). Understanding the elusive mechanisms of tumor-driven immune evasion will aid the refinement of existing cancer immunotherapy strategies and identify novel treatments. To date, preclinical animal models that closely model human cancer and, in particular, include examination of the immune-suppressive mechanisms used by cancer cells have been under-characterized. The identification and use of such models should allow better predictions of successful human responses to immunotherapy.Chronic lymphocytic leukemia (CLL) is an ideal model cancer to study immune T cells that have been exposed to circulating tumor B cells and is associated with immune dysfunction. CLL is the most common adult leukemia in North America and Europe and is currently incurable. Immunotherapeutic strategies are believed to represent a promising treatment modality for this disease if immune suppression can be controlled (3). Extensive research has been carried out using CLL human patient cells, including the characterization of altered gene and proteinexpression profiles (4) and suppressed functional responses in patient T cells compared to healthy-donor T cells (1, 5).We sought to determine whether development of leukemia in the well-established E -TCL1 transgenic murine model of CLL (6) would induce changes in nonmalignant T cells. To examine this, we examined changes in gene-expression profile, protein expression, and function in T cells from E -TCL1 transgenic mice as they developed CLL. We demonstrate that development of CLL in these transgenic mi...

show abstract

Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug

Cited by 392 publications

References 45 publications

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Contact Info

Product

Resources

About