Significance: Patients with microsatellite stable (MSS) pancreatic (PDA) or colorectal cancer (CRC) do not respond to immunotherapy with inhibitors of T cell checkpoints. A possible explanation is suggested by finding that cancer cells in these tumors are coated with the chemokine, CXCL12, and that stimulation of CXCR4, the CXCL12 receptor on immune cells, suppresses directed migration mediated by other chemokine receptors on these cells. We assessed the relevance of these findings by treating patients for seven days with continuous infusion of AMD3100/Plerixafor, a CXCR4 inhibitor. Comparison of pre- and end-of-treatment paired biopsies of metastatic lesions by transcriptomic analysis revealed that AMD3100 induced an integrated immune response that is predictive of a clinical response to T cell checkpoint inhibition.