Chronic lymphocytic leukemia cells induce defective LFA-1–directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide

Ramsay, Alan G.; Evans, Rachel; Kiaii, Shahryar; Svensson, Lena; Hogg, Nancy; Gribben, John G.

doi:10.1182/blood-2012-08-448332

Cited by 113 publications

(102 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recent data have shown that freshly isolated CLL T cells express high levels of the synapse regulators CD272 and CD279 and defective synapse formation compared with normal T cells (22,(42)(43)(44), in part explaining the poor T cell-mediated immune response in these patients (21,45,46). We confirmed in this study that CD272 and CD279 are more highly expressed on T cells from CLL patients compared with normal donors.…”

Section: Discussionsupporting

confidence: 80%

A Novel Method Using Blinatumomab for Efficient, Clinical-Grade Expansion of Polyclonal T Cells for Adoptive Immunotherapy

Golay

D'Amico

Borleri

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Current treatment of chronic lymphocytic leukemia (CLL) patients often results in life-threatening immunosuppression. Furthermore, CLL is still an incurable disease due to the persistence of residual leukemic cells. These patients may therefore benefit from immunotherapy approaches aimed at immunoreconstitution and/or the elimination of residual disease following chemotherapy. For these purposes, we designed a simple GMP-compliant protocol for ex vivo expansion of normal T cells from CLL patients’ peripheral blood for adoptive therapy, using bispecific Ab blinatumomab (CD3 × CD19), acting both as T cell stimulator and CLL depletion agent, and human rIL-2. Starting from only 10 ml CLL peripheral blood, a mean 515 × 106 CD3+ T cells were expanded in 3 wk. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4+ and CD8+ and mostly effector and central memory cells. The Th1 subset was slightly prevalent over Th2, whereas Th17 and T regulatory cells were <1%. CMV-specific clones were detected in equivalent proportion before and after expansion. Interestingly, BET cells had normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were cytotoxic against CD19+ targets in presence of blinatumomab in vitro. In support of their functional capacity, we observed that BET, in combination with blinatumomab, had significant therapeutic activity in a systemic human diffuse large B lymphoma model in NOD-SCID mice. We propose BET as a therapeutic tool for immunoreconstitution of heavily immunosuppressed CLL patients and, in combination with bispecific Ab, as antitumor immunotherapy.

show abstract

Section: Discussionsupporting

confidence: 80%

A Novel Method Using Blinatumomab for Efficient, Clinical-Grade Expansion of Polyclonal T Cells for Adoptive Immunotherapy

Golay

D'Amico

Borleri

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…2 Our previous work demonstrated that T cells from CLL patients show highly impaired immune synapse formation, cytotoxic function, and T-cell adhesion/migration resulting from ineffective regulation of actin-cytoskeleton remodeling. [3][4][5][6] This is mediated by aberrant expression of several inhibitory receptors on CLL cells, prominently PD-L1 (CD274). 7 The corresponding binding partner of PD-L1, PD-1 (CD279), is a major inhibitory receptor associated with T-cell exhaustion, a state of functional hyporesponsiveness caused by chronic infections.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of PD-L1/PD-1–mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model

McClanahan

Riches

Miller

et al. 2015

Blood

Self Cite

104

View full text Add to dashboard Cite

Key Points• PD-L1/PD-1-mediated CD8T-cell dysfunction develops with CLL in different organs, and similarities to agingrelated immune defects exist.• PD-1 1 normal T cells have markedly different effector functions than PD-1 1 CLL T cells.T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Em-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3

show abstract

“…29,35,36 Similarly, lenalidomide was reported to target Rho GTPase signaling and to promote Rap1 trafficking to the membrane, restoring the adhesion and motility function of T cells from CLL patients. 16 Nevertheless, we observed that lenalidomide reduces the migratory capacity of monocytes derived from CLL patients. Since lenalidomide does not affect the viability of monocytes and the expression of chemokine receptors, its inhibitory effect on migration is most likely related to intracellular modification of cytoskeletal molecules.…”

Section: Discussionmentioning

confidence: 69%

“…IMiDs were shown to increase migration of normal monocytes and to repair motility dysfunction of T cells from CLL patients. 16,24 Conversely, IMiDs impaired migration capability of CLL cells and endothelial cells. 17,25 To…”

Section: Lenalidomide Improves Adhesion and Impairs Migration Of Cllmentioning

confidence: 99%

“…13 By in vitro studies and in the TCL1 mouse model for CLL, lenalidomide was shown to reverse defects in adhesion and motility functions, as well as in immunological synapse formation between CLL and T cells, by modulating several cytoskeletal molecules. [14][15][16] Recently, lenalidomide was also shown to interfere with the mutualistic interaction between CLL and NLCs. 17 Together these findings prompted us to investigate the functional effects of lenalidomide on NLCs in CLL.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

et al. 2014

View full text Add to dashboard Cite

Patients and samplesWritten informed consent was obtained in accordance with the Declaration of Helsinki with a protocol approved by the local Institutional Review Board. CD14 + monocytes were obtained by immunomagnetic selection. To generate NLCs, PBMCs from CLL patients were cultured (10 7 /mL) as previously described. 18Lenalidomide was used at the clinically relevant doses of 0.5 mM, 1 mM and 10 mM as in previous studies.

show abstract

Chronic lymphocytic leukemia cells induce defective LFA-1–directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide

Abstract: Key Points CLL cells induce defects in T-cell LFA-1–mediated migration by altering Rho GTPase activation signaling, downregulating RhoA and Rac1, and upregulating Cdc42. Lenalidomide repairs these T-cell defects by restoring normal Rho GTPase activation signaling.

Cited by 113 publications

References 44 publications

A Novel Method Using Blinatumomab for Efficient, Clinical-Grade Expansion of Polyclonal T Cells for Adoptive Immunotherapy

A Novel Method Using Blinatumomab for Efficient, Clinical-Grade Expansion of Polyclonal T Cells for Adoptive Immunotherapy

Mechanisms of PD-L1/PD-1–mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

Contact Info

Product

Resources

About