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Sci Adv. 2019 Feb 20;5(2):eaav2437. doi: 10.1126/sciadv.aav2437. eCollection 2019 Feb.

Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy.

Author information

1
Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
2
Bristol-Myers Squibb, Lawrenceville, NJ, USA.
3
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
4
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
5
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA.
6
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA.
7
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
8
Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada.
9
Bristol-Myers Squibb, Redwood City, CA, USA.
10
Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.

Abstract

While a fraction of cancer patients treated with anti-PD-1 show durable therapeutic responses, most remain unresponsive, highlighting the need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti-PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies-bladder, breast, colon, sarcoma, and melanoma-we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, led to tumor load reduction. RNA-seq and CyTOF analysis revealed higher CD8+ T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.

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