CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
Most tumor-associated macrophages (TAMs), which are abundant in the tumor microenvironment, demonstrate an immunosuppressive phenotype and contribute to tumor progression, treatment resistance and poor clinical outcomes1,2. Due to their functional plasticity, these cells could be reprogrammed to acquire a pro-inflammatory phenotype and promote tumor clearance1. Several therapeutic approaches targeting TAMs to alleviate their immunosuppressive properties or to harness their tumoricidal capacities have been developed3,4. Inhibition of interactions between phagocytic inhibitor receptors on macrophages and "dont eat me signals" on cancer cells, which promotes cancer cell engulfment, showed therapeutic benefits for several tumor types4-6. Investigating mechanisms involved in macrophage-mediated phagocytosis of tumor cells, we demonstrate here a key role for the cyclin-dependent kinase inhibitor CDKN1A (p21). Through transcriptional repression of SIRP (Signal-Regularity Protein ), which encodes a phagocytic inhibitor, CDKN1A promotes the ability of monocyte-derived macrophages (MDMs) to engulf leukemic cells. In turn, these MDMs acquire a pro-inflammatory phenotype that extends to surrounding MDMs in an Interferon {gamma} (IFN{gamma})-dependent manner. Human monocytes genetically engineered to overexpress p21 (p21TD-Mo) differentiate into anti-inflammatory MDMs that are primed for leukemic cell phagocytosis when transferred into mice xenografted with patient-derived T-cell acute lymphoblastic leukemia (T-ALL) cells. After leukemic cell engulfment, engineered macrophages undergo a pro-inflammatory activation, reducing leukemic burden and substantially prolonging survival of mice. These results reveal p21 as a trigger of phagocytosis-guided pro-inflammatory reprogramming of TAMs and demonstrate the potential for p21TD-Mo-based cell therapy in cancer immunotherapy.