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

Science Advances
Megan M TuDan Theodorescu

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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Citations

Jul 5, 2019·Pigment Cell & Melanoma Research·Coralie Reger de MouraFanélie Jouenne
Mar 1, 2020·International Journal of Molecular Sciences·Linda Tran, Dan Theodorescu
Mar 3, 2020·Frontiers in Oncology·Marie LafitteSerge Roche
May 24, 2020·Scientific Reports·Katherine Watkins GreesonCharles A Easley
Nov 29, 2020·Communications Biology·Megan M TuDan Theodorescu
Jan 13, 2021·Cancers·Haitang YangSean R R Hall
Dec 4, 2020·Nature Reviews. Cancer·Linda TranDan Theodorescu
Feb 17, 2021·Nature Reviews. Cancer·Thomas R Cox
Apr 4, 2021·International Journal of Molecular Sciences·Florus C de JongDan Theodorescu
Apr 20, 2021·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·M F TolbaS M Tolaney
Jun 3, 2021·International Journal of Molecular Sciences·Bo Young JeongHoi Young Lee
Jul 3, 2021·International Journal of Molecular Sciences·Ahmed ElkamhawyKyeong Lee
Aug 10, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Fan TangXia-Wei Wei
Sep 17, 2021·Current Cancer Drug Targets·Anna KasperskaŁukasz Szylber

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Methods Mentioned

BETA
RNA-seq
PCR
Assay
gene knockdown
electrophoresis

Clinical Trials Mentioned

NCT02750514

Software Mentioned

PhenoGraph
VariantFiltration
HaplotypeCaller
cytofkit
GSEA
Bowtie 2
Ensembl
SnpEff
limma R package
GATK

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