Single cell RNA sequencing reveals C5aR1 inhibition to selectively target pro-tumorigenic M2 macrophages reversing PARP inhibitor resistance

Abstract

Abstract Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient thus requiring the deployment of combination therapies that can prevent or reverse PARPi resistance. We thus explored mechanisms underlying sensitivity and resistance to PARPi using two intrinsically sensitive and resistant syngeneic murine breast cancer models. Our data indicate that the PARPi-sensitive tumor model has a high ratio of M1 anti-tumor/M2 pro-tumor macrophages with the M1/M2 ratio being increased by PARPi. In contrast the PARPi-resistant tumor model had very low levels of M1 macrophages and thus a low M1/M2 ratio that was not altered by PARPi. Transplantation of the PARPi-sensitive and the PARPi-resistant tumor in opposite mammary fat pads results in accumulation of M2 macrophages in the sensitive tumor, rendering the sensitive tumor PARPi resistant suggesting that transit of M2 macrophages could contribute to resistance across distant sites both within and between tumors. C5ar1 and Rps19/C5ar1 signaling are selectively elevated in the M2 macrophages that are associated with PARPi resistance. Indeed, C5aR1 positive cells were sufficient to transfer resistance to PARPi. Strikingly targeting C5aR1 decreased M2 macrophage numbers, while sparing M1 macrophages rendering PARPi-resistant tumors sensitive to PARPi in a CD8 T cell dependent manner. Consistent with the murine data, high C5aR1 levels in human breast cancers are associated with a poor response to immune checkpoint blockade. Thus, targeting C5aR1 may represent an approach to selectively deplete M2 macrophages and engender sensitivity to PARPi and potentially other therapies.