Expression of inhibitory receptor ILT3 on neoplastic B cells is associated with lymphoid tissue involvement in chronic lymphocytic leukemia

Colovai, Adriana I.; Tsao, Lawrence; Wang, Su; Lin, Hai; Wang, Chuan; Seki, Tetsunori; Fisher, Julie Gottlieb; Menes, Manuel; Bhagat, Govind; Alobeid, Bachir; Suciu‐Foca, Nicole

doi:10.1002/cyto.b.20164

Cited by 49 publications

(38 citation statements)

References 29 publications

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“…Ectopic expression of ILT3 by tumor cells, as recently found in chronic lymphocytic leukemia, may render tumor cells tolerogenic and provide an alternative source of both mILT3 and sILT3 (49). We cannot discriminate, however, between the possibility that Ts induce up-regulation and release of ILT3 from TAM or, alternatively, that tumor-or TAM-secreted ILT3 binds to the ILT3 ligand on activated CD4 T cells, rendering them anergic and, thus, unable to sustain the differentiation of CD8 ϩ CTL (17).…”

Section: Discussionmentioning

confidence: 90%

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

Suciu‐Foca¹,

Feirt²,

Zhang³

et al. 2007

The Journal of Immunology

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Attempts to enhance patients’ immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8+ T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8+ T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68+ tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.

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Section: Discussionmentioning

confidence: 90%

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

Suciu‐Foca¹,

Feirt²,

Zhang³

et al. 2007

The Journal of Immunology

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“…Membrane-bound ILT3 is expressed on tumor cells in B-cell chronic lymphocytic leukemia (B-CLL), myeloid leukemia, and pancreatic and gastric cancer, and in B-CLL its expression on tumor cells is associated with aggressive growth. 13,37,38 Elevated expression on DCs was found in colorectal cancer patients compared to healthy controls.…”

Section: Ilt3mentioning

confidence: 99%

“…10 An important mediator of the induction of immune tolerance is immunoglobulin-like transcript (ILT) 3 (also known as LILRB4, CD85k, or LIR-5), which is expressed on monocytes and antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs). 11,12 ILT3 expression marks tolerogenic DCs and has been reported to be elevated in APCs of cancer patients 13,14 and decreased in autoimmune diseases. 15,16 ILT3 is believed to signal via its immunoreceptor tyrosine-based inhibitory motifs (ITIMs).…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer

et al. 2015

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Myeloid-derived suppressor cells (MDSCs) play an important role in immune suppression and accumulate under pathologic conditions such as cancer and chronic inflammation. They comprise a heterogeneous population of immature myeloid cells that exert their immunosuppressive function via a variety of mechanisms. Immunoglobulin-like transcript 3 (ILT3) is a receptor containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can be expressed on antigen-presenting cells and is an important regulator of dendritic cell tolerance. ILT3 exists in a membrane-bound and a soluble form and can interact with a yet unidentified ligand on T cells and thereby induce T-cell anergy, regulatory T cells, or T suppressor cells. In this study, we analyzed freshly isolated peripheral blood mononuclear cells (PBMCs) of 105 patients with non-small cell lung cancer and 20 healthy controls and demonstrated for the first time that ILT3 is expressed on MDSCs. We show that increased levels of circulating MDSCs correlate with reduced survival. On the basis of ILT3 cell surface expression, an ILT3 low and ILT3 high population of polymorphonuclear (PMN)-MDSCs could be distinguished. Interestingly, in line with the immunosuppressive function of ILT3 on dendritic cells, patients with an increased proportion of PMN-MDSCs and an increased fraction of the ILT3 high subset had a shorter median survival than patients with elevated PMN-MDSC and a smaller ILT3 high fraction. No correlation between the ILT3 high subset and other immune variables was found. ILT3 expressed on MDSCs might reflect a previously unknown mechanism by which this cell population induces immune suppression and could therefore be an attractive target for immune intervention.

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“…In contrast, knockdown of ILT3 renders dendritic cells more sensitive to TLR signals (27). We have previously shown that ILT3 is a useful marker for the identification of aggressive chronic lymphocytic leukemia (CLL) (30). Although absent on normal B lymphocytes, ILT3 is expressed by leukemic B cells from a subset of CLL patients displaying extensive lymph node involvement.…”

Section: Introductionmentioning

confidence: 99%

Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation

Dobrowolska

Gill

Serban

et al. 2012

Cytometry Part B Clinical

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Background: The diagnosis of AML with monocytic differentiation is limited by the lack of highly sensitive and specific monocytic markers. Immunoglobulin-like transcript 3 (ILT3) is an immune inhibitory receptor expressed by myelomonocytic cells and at high levels by tolerogenic dendritic cells.Methods: Using flow cytometry, we analyzed the expression of ILT3 in 37 patients with AML and 20 patients with no detectable disease.Results: We showed that ILT3 was expressed in all cases of AML displaying monocytic differentiation (FAB M4/M5; N 5 18), but not in AML M1/M2 and M3 (N 5 19; P < 0.0001). Co-expression of ILT3 and immature cell markers, such as CD34 and CD117, was observed in monoblastic leukemia. ILT3 expression was preserved after treatment in M4/M5 patients with refractory or relapsed disease. ILT3 expression was associated with the presence of cytogenetic abnormalities linked to an intermediate prognosis (P 5 0.001). Rare CD45dimCD341CD1171ILT31 cells were identified in noninvolved bone marrow, suggesting that ILT3 expression is acquired at an early stage by normal myelomonocytic precursors.Conclusions: ILT3 is a highly sensitive and specific marker which distinguishes AML with monocytic differentiation from other types of AML. Testing of ILT3 expression should be incorporated into the initial diagnostic work-up and monitoring of patients with AML.

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Expression of inhibitory receptor ILT3 on neoplastic B cells is associated with lymphoid tissue involvement in chronic lymphocytic leukemia

Cited by 49 publications

References 29 publications

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer

Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation

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