Myeloid mechano-metabolic programming restricts anti-tumor immunity

Tharp, K.; Kersten, K.; Maller, O.; timblin, G.; Stashko, C.; Hayward, M.-K.; Berestjuk, I.; ten Hoeve-Scott, J.; Samad, B.; Combes, A.; Weaver, V.

doi:10.1101/2022.07.14.499764

bioRxiv · 10.1101/2022.07.14.499764

Myeloid mechano-metabolic programming restricts anti-tumor immunity

Tharp, K.·Kersten, K.·Maller, O.·timblin, G.·Stashko, C.·Hayward, M.-K.·Berestjuk, I.·ten Hoeve-Scott, J.·Samad, B.·Combes, A.·Weaver, V.

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Abstract

Tumor progression is accompanied by fibrosis, which is associated with diminished anti-tumor immune infiltrate. Here, we demonstrate that tumor infiltrating myeloid cells respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a TGF-beta (TGF{beta})-directed, 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 secrete 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 a myeloid mechano-metabolic programming we identified that creates an inhospitable metabolic milieu for CD8+ T cells.

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Tharp, K., Kersten, K., Maller, O., timblin, G., Stashko, C., Hayward, M.-K., Berestjuk, I., ten Hoeve-Scott, J., Samad, B., Combes, A., Weaver, V.. 2022-07-16. Myeloid mechano-metabolic programming restricts anti-tumor immunity. https://doi.org/10.1101/2022.07.14.499764

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