Abstract 4085: DDR2 inhibition enhances response to anti-PD-1 immunotherapy

Abstract

Therapies targeting PD-1 are used in multiple cancer types. While a fraction of patients show durable therapeutic responses, most remain unresponsive, highlighting an urgent 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, also led to tumor load reduction and in some cases, complete clearance. RNAseq 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. Citation Format: Megan M. Tu, Francis Y. Lee, Robert T. Jones, Abigail K. Kimball, Elizabeth Saravia, Robert F. Graziano, Brianne Coleman, Krista Menard, Jun Yan, Erin Michaud, Han Chang, Hany A. Abdel-Hafiz, Andrii I. Rozhok, Jason E. Duex, Neeraj Agarwal, Ana Chauca-Diaz, Linda K. Johnson, Terry L. Ng, John C. Cambier, Eric T. Clambey, James C. Costello, Alan J. Korman, Dan Theodorescu. DDR2 inhibition enhances response to anti-PD-1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4085.

Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guérin

“…Recently, anti-PD-1 combined with anti-CTLA-4 showed excellent response rates as neoadjuvant therapy in MIBC, and the data indicates this strategy has potential in BCGunresponsive disease as well [56]. Lastly, in vivo studies showed positive synergistic effects on tumor load and increased CD8+ T cell influx when dasatinib (anti-DDR2) was combined PD-L1 blockade [57]. In addition to RNA overexpression of checkpoint proteins in BRS3, we demonstrate an increased expression of DDR2 in post-BCG tumors, thus supporting the potential of anti-PD-L1 combination treatment with anti-DDR2.…”

“…In addition to RNA overexpression of checkpoint proteins in BRS3, we demonstrate an increased expression of DDR2 in post-BCG tumors, thus supporting the potential of anti-PD-L1 combination treatment with anti-DDR2. The latter mechanism is in part due to M2 macrophages via CCL2, in which CCL2 inhibition could improve checkpoint therapy [57,58].…”