We demonstrate that in tumors lacking T-cell infiltration and poorly responsive to fractionated RT, combination with an agonistic αCD40 monoclonal antibody (mAb) results in environmental reprogramming characterized by an increase in IFN-y signaling, activation of Th−1 pathways and increased infiltration of CD8+ T-cells in to the TME, which leads to enhanced tumor control over that observed with RT and αPD−1 combinations. The gene discussed is CD8A; the disease is neoplasm.