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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