(590g) Marrow-Derived & Surface-Engineered Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors

Discher, D. E., University of Pennsylvania
Marrow-derived macrophages are highly phagocytic, but whether they can also be made to traffic into solid tumors and engulf cancer cells is questionable, given well-known limitations of tumor-associated macrophages (TAMs). Here, SIRPa on macrophages from mouse and human marrow was inhibited to block recognition of its CD47 ligand, a ‘‘marker of self’’ on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted. Within days, the tumors regressed, and fluorescence analyses showed that the more the SIRPa-inhibited macrophages engulfed, the more they accumulated within regressing tumors. Human-marrow-derived macrophages engorged on the human tumors, while TAMs were minimally phagocytic, even toward CD47-knockdown tumors. Past studies have opsonized tumors in situ with antibody and/or relied on mouse TAMs but have not injected SIRPa-inhibited cells; also, unlike past injections of anti-CD47, blood parameters remained normal here. Consistent with tumor-selective engorge-and-accumulate processes in vivo, phagocytosis in vitro inhibited macrophage migration through micropores that mimic features of dense 3D tissue. Accumulation of SIRPa-inhibited macrophages in tumors favored tumor regression for 1–2 weeks, but donor macrophages quickly differentiated toward non-phagocytic, high-SIRPa TAMs. Analyses of macrophages on soft (like marrow) or stiff (like solid tumors) collagenous gels demonstrated a stiffness-driven, retinoic acid-modulated upregulation of SIRPa and also a mechanosensitive nuclear marker, lamin-A. Mechanosensitive differentiation was similarly evident in vivo and likely limited the anti-tumor effects, as confirmed by re-initiation of tumor regression by fresh injections of SIRPa-inhibited macrophages. Macrophage motility, phagocytosis, and differentiation in vivo are thus coupled.