Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities

Wölfl, Matthias; Kuball, Jürgen; Ho, William; Nguyen, Hat; Manley, Thomas; Bleakley, Marie; Greenberg, Philip D.

doi:10.1182/blood-2006-11-056168

Cited by 392 publications

(389 citation statements)

References 44 publications

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“…First, CD137 expression can be used for immunomagnetic selection of tumor reactive TILs (38), and subsequent culture of T cells in the presence of CD137 renders more efficacious phenotypic features (39,40). Second, the effector performance (11), survival (10), and memory differentiation (41) can be enhanced by coadministration of the agonist antibody in vivo.…”

Section: Discussionmentioning

confidence: 99%

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Weigelin

Bolaños

Teijeira

et al. 2015

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

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Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.

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Section: Discussionmentioning

confidence: 99%

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Weigelin

Bolaños

Teijeira

et al. 2015

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

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“…Naive [18] and central memory T cells [29] produce no to low amounts of effector molecules and are easily missed if detection of alloreactive T cells is based on cell proliferation or IFN-γ positivity only. With respect to alloreactive naive and central memory cytokine + CD4 + as well as CD8 + T cells, our data are confirmed by a paper by Melenhorst et al [30], who described the alloreactive T cells to be both of the naive and antigen-experienced (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Identification of antigen-reactive T cells by activationinduction expression of co-stimulatory molecules such as CD154 and CD137 has recently enabled identification and isolation of virus-reactive T cells on the single-cell level [16][17][18][19]. We have adapted the CD154 live assay [16,17] and were able to identify alloreactive CD4 + T cells with great sensitivity and specificity in combination with phenotypic and functional analysis on the single-cell level [13].…”

Section: Introductionmentioning

confidence: 99%

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Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Litjens

Wit

Baan

et al. 2013

Clinical and Experimental Immunology

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SummaryDetection and isolation of viable alloreactive T cells at the single-cell level requires a cell surface marker induced specifically upon T cell receptor activation. In this study, a member of the tumour necrosis factor receptor (TNFR)-family, CD137 (4-1BB) was investigated for its potential to identify the total pool of circulating alloreactive T cells. Optimal conditions for sensitive and specific detection of allogeneic-induced CD137 expression on circulating T cells were established. Thereafter, CD137+ alloreactive T cells were phenotypically and functionally characterized by multi-parameter flow cytometry. Alloantigen-induced CD137 expression identified both alloreactive CD8 + T cells (mean ± standard error of the mean: 0·21 ± 0·07%) and alloreactive CD4 + T cells (0·21 ± 0·05%). CD137 + alloreactive T cells were detected in different T cell subsets, including naive T cells, but were found preferentially in CD28+ T cells and not in the terminally differentiated T cell subset. Upon allogeneic (re-)stimulation, the cytokine-producing as well as proliferative capacity of T cells resided mainly within the CD137-expressing fraction. About 10% of the CD137 + alloreactive T cells produced any combination of interferon (IFN)-γ, interleukin (IL)-2 and TNF-α. Polyfunctional alloreactive T cells, defined by multiple cytokine expression, were observed infrequently. In conclusion, activation-induced CD137 expression is a fast assay allowing for detection and functional analysis of the total alloreactive T cell compartment at the single-cell level by multiparameter flow cytometry.

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“…The procedure was conducted as previously described with some minor adjustments. 15,27,28 The HLA type of each patient was known, and peptides that matched the HLA type were chosen from the list of previously described tumor-associated Ags selected from supplemental Table 2. (Alta Bioscience) The frequency of CD137 ϩ Ag-specific T cells was calculated as a percentage of the total CD8 ϩ T-cell pool from the estimates before enrichment estimates.…”

Section: Quantification Of Circulating Tumor-specific Cd8 ؉ T Cellsmentioning

confidence: 99%

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Goodyear

Dennis

Jilani

et al. 2012

Blood

365

257

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Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities

Abstract: CD137 is a member of the TNFR-family

Cited by 392 publications

References 44 publications

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

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