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

// Steven A. Greenberg 1, 2 , Sek Won Kong 2, 3 , Evan Thompson 4 and Stefano V. Gulla 4 1 Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 2 Computational Health Informatics Program, Boston Children’s Hospital, Boston, MA, USA 3 Department of Pediatrics, Harvard Medical School, Boston, MA, USA 4 Abcuro, Inc., Newton, MA, USA Correspondence to: Steven A. Greenberg, email: sagreenberg@bwh.harvard.edu Keywords: immune checkpoint receptor; immunotherapy; KLRG1; co-inhibitory receptor; murine cancer models Received: December 12, 2018     Accepted: January 21, 2019     Published: February 15, 2019 ABSTRACT Background: 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. Methods: We 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. Results: In 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). Conclusions: 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. The mechanism of efficacy of KLRG1 blockade in murine models remains to be determined.