Myeloid mechano-metabolic programming restricts anti-tumor immunity

Abstract

Tumor progression ensues when the immune system fails to mount a productive anti-tumor response. Inappropriate programming of myeloid cells associates with tissue fibrosis and is accompanied by impaired T cell anti-tumor responses. Here, we demonstrate that myeloid cells respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a wound-healing associated collagen biosynthesis program. A collateral effect of this programming is an untenable metabolic milieu for productive CD8 T cell anti-tumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline, and excrete ornithine that compromises CD8 T cell function. Thus, a stiff and fibrotic TME may impede anti-tumor immunity not only by direct physical exclusion of CD8 T cells, but also via secondary effects of the myeloid mechano-metabolic programming described here that creates an inhospitable metabolic milieu for CD8 T cells.

The microenvironment dictates glycocalyx construction and immune surveillance

“…We also identified medium-independent mechanosensitive metabolic responses including the metabolism of arginine to ornithine ( Fig. S3D ) 10 and creatinine to phosphocreatine ( Fig. S3E ) 5 .…”

“…Cell-extrinsic mechanical properties affect adhesion and cytoskeletal dynamics, which have an emerging role in the regulation of metabolism [4][5][6][7][8][9] . Mechanical regulation of metabolism can reciprocally tune the physical properties of cells and tissues by rewiring metabolism to synthesize structural macromolecules like the extracellular matrix (ECM) 10 or glycocalyx [11][12][13] , a pericellular matrix composed of glycoproteins and glycolipids that is especially apparent on the surface of endothelial and epithelial cells. This type of "mechanoreciprocity" may serve to buffer mechanical stresses by reducing the need for energetically demanding cytoskeletal responses in favor of passive physical buffering via the ECM or glycocalyx 14,15 .…”

Coenzyme A governs proinflammatory macrophage metabolism

“…In solid tumors such as breast cancer, this response protects and promotes tumor growth, with TAMs polarizing towards a wound-healing, TGFβ-producing, pro-resolution phenotype. These TAMs promote tumor fibrosis via activation of stromal cells ( 33 ), and acquisition of a collagen-biosynthetic, immunosuppressive phenotype ( 67 ). The nutrient fluxes in theses TAM are likely incompatible with the fluxes supporting a proinflammatory phenotype, as the biosynthetic goals of these macrophages (collagen production for repair vs. proinflammatory mediator production for defense) are divergent.…”

“…Immune suppression is a barrier to the treatment of inflammatory diseases, as both sterile and non-sterile PAMP/DAMP-triggered inflammation have evolved strong negative feedback mechanisms to both protect the host, and transition responses to an injury-reparative phase. In solid tumors including breast cancer, this response promotes tumor growth, with TAMs polarizing towards a wound-healing, TGFβ-producing, collagen-biosynthetic, immunosuppressive phenotype ( 97 ). The nutrient fluxes in TAMs are likely incompatible with supporting a proinflammatory phenotype, as the biosynthetic goals of these macrophages (collagen production for repair vs. proinflammatory mediator production for defense) are divergent.…”

Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading

“…Arg1 enzymatically converts arginine to urea and ornithine, and macrophages expressing Arg1 secrete ornithine into the tissue microenvrionment 22 . Ornithine can serve as a substrate for the synthesis of proline 23 , a major constituent of collagens.…”