Scientific Publications Database
Article Title: Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapyAuthors: Tu, Megan M.; Lee, Francis Y. F.; Jones, Robert T.; Kimball, Abigail K.; Saravia, Elizabeth; Graziano, Robert F.; Coleman, Brianne; Menard, Krista; Yan, Jun; Michaud, Erin; Chang, Han; Abdel-Hafiz, Hany A.; Rozhok, Andrii, I; Duex, Jason E.; Agarwal, Neeraj; Chauca-Diaz, Ana; Johnson, Linda K.; Ng, Terry L.; Cambier, John C.; Clambey, Eric T.; Costello, James C.; Korman, Alan J.; Theodorescu, Dan
Journal: SCIENCE ADVANCES Volume 5 Issue 2
Date of Publication:2019
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.