Related Experiment Video
Updated: Jul 5, 2025
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes
Bimarzhan Assatova1,2, Robert Willim3,4, Christopher Trevisani2,5
1Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Purpose:
Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.
Experimental Design:
Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.
Results:
Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy.
Conclusions:
Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.
Insights
A novel antibody targeting KLRG1 (killer cell lectin-like receptor 1) shows promise for treating mature T-cell and NK-cell neoplasms. This antibody, mAb208, effectively depletes tumor cells and, when combined with other therapies, extends survival in preclinical models.
Area of Science:
- Immunology
- Oncology
- Therapeutic Development
Background:
- Mature T-cell and NK-cell neoplasms are a diverse group of hematologic malignancies.
- Identifying specific targets for novel therapeutic strategies is crucial for improving patient outcomes.
Purpose of the Study:
- To develop and validate a novel therapeutic strategy targeting KLRG1 (killer cell lectin-like receptor 1) in mature T-cell and NK-cell neoplasms.
- To investigate the efficacy of an anti-KLRG1 monoclonal antibody (mAb208) in preclinical models.
Main Methods:
- Screening and validation using primary specimens, cell lines, and xenograft models.
- Functional assessment of anti-KLRG1 monoclonal antibody (mAb208) via ADCC, ADCP, and CDC mechanisms.
- Combination therapy studies with anti-CD47 mAb and PI3K-δ/γ inhibitor duvelisib.
Main Results:
- Surface KLRG1 is highly expressed on tumor cells in extranodal NK/T-cell lymphoma, T-prolymphocytic leukemia, and gamma/delta T-cell lymphoma.
- mAb208 effectively depleted KLRG1+ T-cell lymphoma cells through ADCC, ADCP, and CDC.
- Combination therapy with mAb208, anti-CD47 mAb, and duvelisib extended survival in xenograft models.
Conclusions:
- Anti-KLRG1 antibody therapy demonstrates potential for treating KLRG1-expressing T-cell and NK-cell neoplasms.
- Combined therapeutic strategies involving antibodies and PI3K inhibitors may offer broader treatment benefits.
- Further investigation into macrophage roles in antibody efficacy is warranted.
