Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models.

Steven A Greenberg,Evan Thompson,Stefano V Gulla,Sek Won Kong

doi:10.18632/oncotarget.26659

Steven A Greenberg, Evan Thompson + Show 2 more

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https://doi.org/10.18632/oncotarget.26659

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Abstract

BackgroundKLRG1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on late-differentiated effector and effector memory CD8+ T and NK cells. Targeting of KLRG1 neutralization in murine cancer models has not previously been reported.MethodsWe studied KLRG1 expression in human blood and tumor samples from available genomic datasets. Anti-KLRG1 neutralizing antibody was studied in the murine 4T1 breast cancer as monotherapy, and in the MC38 colon cancer and B16F10 melanoma models as combination therapy with anti-PD-1 antibody.ResultsIn human blood and tumor samples, KLRG1 expression is aligned with cytotoxic T and NK cell differentiation, and upregulated in human tumor samples after a variety of therapies, potentially contributing to adaptive resistance. In in vivo murine models, anti-KLRG1 antibody monotherapy in the 4T1 breast cancer model reduced lung metastases (decreased lung weights p=0.04; decreased nodule count p=0.002), while anti-KLRG1 + anti-PD-1 combination therapy in the MC38 colon cancer and B16F10 melanoma models produced synergistic benefit greater than anti-PD-1 alone for tumor volume (MC38 p=0.01; B16F10 p=0.007) and survival (MC38 p=0.02; B16F10 p=0.002).ConclusionsThese studies provide the first evidence that inhibition of the KLRG1 pathway enhances immune control of cancer in murine models, and provide target validation for KLRG1 targeting of human cancer. The mechanism of efficacy of KLRG1 blockade in murine models remains to be determined.

Highlights

Killer cell lectin-like receptor G1 (KLRG1) is a co-inhibitory, or immune checkpoint, receptor inhibiting the activity of T and NK cells
In in vivo murine models, anti-KLRG1 antibody monotherapy in the 4T1 breast cancer model reduced lung metastases, while anti-KLRG1 + anti-PD-1 combination therapy in the MC38 colon cancer and B16F10 melanoma models produced synergistic benefit greater than antiPD-1 alone for tumor volume (MC38 p=0.01; B16F10 p=0.007) and survival (MC38 p=0.02; B16F10 p=0.002). These studies provide the first evidence that inhibition of the KLRG1 pathway enhances immune control of cancer in murine models, and provide target validation for KLRG1 targeting of human cancer
KLRG1 is preferentially expressed on effector and effector memory CD8 T cells and NK cells and differentially expressed than PD-1

Summary

Introduction

Killer cell lectin-like receptor G1 (KLRG1) is a co-inhibitory, or immune checkpoint, receptor inhibiting the activity of T and NK cells. Whereas targeting of other co-inhibitory receptors for applications in oncology has gained widespread interest [3,4,5], including multiple FDA approvals for targeting CTLA-4, PD-1, and its ligand PD-L1, less attention has been focused on the therapeutic potential of KLRG1 modulation. Unlike the obvious enhanced immune activation present in CTLA-4 and PD-1 gene knockout mice [6, 7], KLRG1 knockout mice initially were found to have no abnormal features [8], though were subsequently found to have enhanced immunity in a tuberculosis challenge model [9]. KLRG1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on late-differentiated effector and effector memory CD8+ T and NK cells. Targeting of KLRG1 neutralization in murine cancer models has not previously been reported

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