Mechanosensing of Solid Tumors by Cancer-Attacking Macrophages

Abstract

The physical biology of immune cell interactions with solid tumors has many facets, from tissue and cell levels down to key molecules. Macrophages are highly phagocytic, especially when derived from marrow, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). Here, a ‘self’ recognition receptor on macrophages, termed SIRPa, was inhibited to block binding at a phagocytic synapse to its membrane ligand, the ‘‘marker of self’’ CD47 found on all other cells. The modified macrophages were then systemically injected into mice with fluorescent human tumors that were also antibody targeted. Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the 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. Super-resolution imaging and mathematical modeling at multiple scales deepen insight into the key processes. 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 upregulation of SIRPa and the 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 and physically modulated.