Using a mouse model of mammary tumorigenesis, Tharp et al. showed that TAM-dependent development of a stiff fibrotic TME led to elevated expression of collagen ECM synthesis genes. Collagen transcript expression by infiltrating myeloid cells was shown to correlate with reduced survival of patients with breast cancer. TAMs in stiff fibrotic tumors effected an autocrine TGFβ1 response that synergized with mechanosensitive regulation from the fibrotic stroma to induce enhanced metabolism of arginine to proline for collagen ECM biosynthesis and immunosuppressive ornithine, which additionally hindered CD8+ T cell antitumor and ICB responses.
Contributed by Paula Hochman
ABSTRACT: Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies.
Author Info: (1) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (2) Department of Pathology, Universit
Author Info: (1) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (2) Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. (3) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (4) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (5) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (6) Institute for Research in Biomedicine, Université della Svizzera italiana, Bellinzona, Switzerland. (7) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. (8) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (9) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. (10) UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA. (11) Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. UCSF CoLabs, University of California San Francisco, San Francisco, CA, USA. (12) Department of Pathology, Western General Hospital, NHS Lothian, Edinburgh, UK. (13) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. Department of Cell and Developmental Biology, Cancer Biology Program, University of Michigan, Ann Arbor, MI, USA. (14) Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. (15) Institute for Research in Biomedicine, Université della Svizzera italiana, Bellinzona, Switzerland. (16) Department of Pathology, University of California San Francisco, San Francisco, CA, USA. ImmunoX Initiative, University of California San Francisco, San Francisco, CA, USA. UCSF CoLabs, University of California San Francisco, San Francisco, CA, USA. Department of Medicine, University of California San Francisco, San Francisco, CA, USA. (17) Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA. valerie.weaver@ucsf.edu. Department of Bioengineering and Therapeutic Sciences and Department of Radiation Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and The Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. valerie.weaver@ucsf.edu.
