Myeloid mechano-metabolic programming restricts anti-tumor immunity

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 (TGFβ)-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.

[1]  J. Crawford,et al.  LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages , 2022, Nature.

[2]  P. Allavena,et al.  Macrophages as tools and targets in cancer therapy , 2022, Nature Reviews Drug Discovery.

[3]  Jordan F Hastings,et al.  Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis , 2022, Nature Communications.

[4]  M. Lanuti,et al.  Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes. , 2022, Cancer cell.

[5]  Z. Nwosu,et al.  Arginase 1 is a key driver of immune suppression in pancreatic cancer , 2022, bioRxiv.

[6]  D. Hume,et al.  Tumor-associated macrophage heterogeneity is driven by tissue territories in breast cancer. , 2022, Cell reports.

[7]  Jonathan D. Curtis,et al.  A common framework of monocyte-derived macrophage activation , 2022, Science Immunology.

[8]  Cynthia A. Reinhart-King,et al.  Matrix stiffness enhances cancer-macrophage interactions and M2-like macrophage accumulation in the breast tumor microenvironment. , 2022, Acta biomaterialia.

[9]  A. Chinnaiyan,et al.  Metabolism drives macrophage heterogeneity in the tumor microenvironment , 2022, Cell reports.

[10]  E. Nakakura,et al.  Discovering dominant tumor immune archetypes in a pan-cancer census , 2021, Cell.

[11]  M. Pujana,et al.  Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion , 2021, Nature.

[12]  Rakesh K. Arya,et al.  Mechanosensing by TRPV4 mediates stiffness-induced foreign body response and giant cell formation , 2021, Science Signaling.

[13]  Ansuman T. Satpathy,et al.  Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer , 2021, bioRxiv.

[14]  P. Gimotty,et al.  Activating a collaborative innate-adaptive immune response to control metastasis. , 2021, Cancer cell.

[15]  E. Pearce,et al.  Metabolic orchestration of the wound healing response. , 2021, Cell metabolism.

[16]  M. Krummel,et al.  Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer , 2021, bioRxiv.

[17]  R. Geiger,et al.  Metabolic modulation of tumours with engineered bacteria for immunotherapy , 2021, Nature.

[18]  A. Ewald,et al.  Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis. , 2021, Cell metabolism.

[19]  D. Griggs,et al.  Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β , 2021, Nature Biomedical Engineering.

[20]  N. Almog,et al.  Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. , 2021, Cancer cell.

[21]  R. Deberardinis,et al.  Mitochondrial NADP+ is essential for proline biosynthesis during cell growth , 2021, Nature Metabolism.

[22]  Greg M. Delgoffe,et al.  Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion , 2021, Nature immunology.

[23]  A. A. Mehl,et al.  Hard-to-heal wounds: a randomised trial of an oral proline-containing supplement to aid repair. , 2021, Journal of wound care.

[24]  D. Nomura,et al.  Mitohormesis reprograms macrophage metabolism to enforce tolerance , 2020, Nature Metabolism.

[25]  Y. Saeys,et al.  Macrophages are metabolically heterogeneous within the tumor microenvironment. , 2020, Cell reports.

[26]  L. Coussens,et al.  Tumor-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression , 2020, Nature Materials.

[27]  S. Naber,et al.  Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis , 2020, Science Advances.

[28]  D. Sabatini,et al.  CRISPR screens in physiologic medium reveal conditionally essential genes in human cells , 2020, bioRxiv.

[29]  M. V. Heiden,et al.  Cell Programmed Nutrient Partitioning in the Tumor Microenvironment , 2020, bioRxiv.

[30]  J. Powell,et al.  Metabolism of immune cells in cancer , 2020, Nature Reviews Cancer.

[31]  Scott B. Thompson,et al.  Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity , 2020, eLife.

[32]  K. Pogoda,et al.  Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment , 2020, bioRxiv.

[33]  D. Nowis,et al.  Myeloid Cell-Derived Arginase in Cancer Immune Response , 2020, Frontiers in Immunology.

[34]  A. Lim,et al.  The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy , 2020, eLife.

[35]  J. Burdick,et al.  Engineered Biomaterial Platforms to Study Fibrosis , 2020, Advanced healthcare materials.

[36]  N. Krogan,et al.  Adhesion-mediated mechanosignaling forces mitohormesis , 2020, bioRxiv.

[37]  C. Thompson,et al.  Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress , 2020, The EMBO journal.

[38]  Le A. Trinh,et al.  Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair , 2020, Nature Communications.

[39]  R. Jain,et al.  A framework for advancing our understanding of cancer-associated fibroblasts , 2020, Nature Reviews Cancer.

[40]  Keiryn L. Bennett,et al.  Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function , 2019, Immunity.

[41]  Takla Griss,et al.  Metabolic Profiling Using Stable Isotope Tracing Reveals Distinct Patterns of Glucose Utilization by Physiologically Activated CD8+ T Cells. , 2019, Immunity.

[42]  M. Lenardo,et al.  Human Plasma-like Medium Improves T Lymphocyte Activation , 2019, bioRxiv.

[43]  U. Alon,et al.  Principles of Cell Circuits for Tissue Repair and Fibrosis , 2019, bioRxiv.

[44]  B. Hinz,et al.  Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix , 2019, Nature Communications.

[45]  C. Mierke,et al.  Design of biomimetic collagen matrices by reagent-free electron beam induced crosslinking: Structure-property relationships and cellular response , 2019, Materials & Design.

[46]  Olga Tanaseichuk,et al.  Metascape provides a biologist-oriented resource for the analysis of systems-level datasets , 2019, Nature Communications.

[47]  P. Spellman,et al.  Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets , 2019, Cancer cell.

[48]  Joerg M. Buescher,et al.  Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species–mediated DNA damage , 2019, Nature Immunology.

[49]  G. Xiao,et al.  Kindlin-2 links mechano-environment to proline synthesis and tumor growth , 2019, Nature Communications.

[50]  M. V. Vander Heiden,et al.  Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability , 2018, bioRxiv.

[51]  P. Bose,et al.  TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure , 2018, Nature Communications.

[52]  Deshka S. Foster,et al.  The evolving relationship of wound healing and tumor stroma. , 2018, JCI insight.

[53]  Arkaitz Carracedo,et al.  Rewiring urea cycle metabolism in cancer to support anabolism , 2018, Nature Reviews Cancer.

[54]  N. Bercovici,et al.  Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment , 2018, Proceedings of the National Academy of Sciences.

[55]  R. Weinberg,et al.  Understanding the tumor immune microenvironment (TIME) for effective therapy , 2018, Nature Medicine.

[56]  Sanjay Kumar,et al.  Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues. , 2018, Cell metabolism.

[57]  Camille Stephan-Otto Attolini,et al.  TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis , 2018, Nature.

[58]  R. Bourgon,et al.  TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells , 2018, Nature.

[59]  Cheong-Hee Chang,et al.  The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease , 2018, Immune network.

[60]  L. Galluzzi,et al.  The spectrum of T cell metabolism in health and disease , 2017, Nature Reviews Immunology.

[61]  B. Becher,et al.  The Cytokine TGF‐&bgr; Promotes the Development and Homeostasis of Alveolar Macrophages , 2017, Immunity.

[62]  Guillaume Jacquemet,et al.  Cell-derived matrices for studying cell proliferation and directional migration in a complex 3D microenvironment , 2017, Nature Protocols.

[63]  C. Ries,et al.  Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy , 2017, Journal of Immunotherapy for Cancer.

[64]  Hong Jiang,et al.  Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy , 2017, Cancer Immunology, Immunotherapy.

[65]  T. Mak,et al.  Glutathione Primes T Cell Metabolism for Inflammation , 2017, Immunity.

[66]  Xin Gao,et al.  Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase , 2017, Cell.

[67]  Shawn P. Carey,et al.  Three-dimensional collagen matrix induces a mechanosensitive invasive epithelial phenotype , 2017, Scientific Reports.

[68]  C. Rock,et al.  T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions* , 2016, The Journal of Biological Chemistry.

[69]  Z. Halpern,et al.  Tumor macrophages are pivotal constructors of tumor collagenous matrix , 2016, The Journal of experimental medicine.

[70]  M. Mann,et al.  L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity , 2016, Cell.

[71]  D. Gabrilovich,et al.  The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. , 2016, Trends in immunology.

[72]  A. Ribas,et al.  Combination cancer immunotherapies tailored to the tumour microenvironment , 2016, Nature Reviews Clinical Oncology.

[73]  S. V. van Putten,et al.  3,4-Dihydroxy-L-Phenylalanine as a Novel Covalent Linker of Extracellular Matrix Proteins to Polyacrylamide Hydrogels with a Tunable Stiffness. , 2016, Tissue engineering. Part C, Methods.

[74]  Umar Mahmood,et al.  Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. , 2015, Cancer cell.

[75]  Catherine C. Park,et al.  Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[76]  K. Kissa,et al.  Identification of polarized macrophage subsets in zebrafish , 2015, eLife.

[77]  D. Fearon,et al.  T cell exclusion, immune privilege, and the tumor microenvironment , 2015, Science.

[78]  D. Linehan,et al.  CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. , 2015, Cancer research.

[79]  V. Weaver,et al.  The extracellular matrix modulates the hallmarks of cancer , 2014, EMBO reports.

[80]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[81]  Guanqing Ou,et al.  Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression , 2014, Nature Medicine.

[82]  Sebastian Amigorena,et al.  Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen-Presenting Cells Critical for T Cell Immunity. , 2014, Cancer cell.

[83]  J. Weiss,et al.  TGF-β signaling in myeloid cells is required for tumor metastasis. , 2013, Cancer discovery.

[84]  M. Zucchetti,et al.  Role of macrophage targeting in the antitumor activity of trabectedin. , 2013, Cancer cell.

[85]  D. Gabrilovich,et al.  Coordinated regulation of myeloid cells by tumours , 2012, Nature Reviews Immunology.

[86]  Mikala Egeblad,et al.  Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. , 2012, Cancer cell.

[87]  Christopher S. Chen,et al.  Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition , 2012, Molecular biology of the cell.

[88]  Jinyan Wang,et al.  Transition of tumor-associated macrophages from MHC class IIhi to MHC class IIlow mediates tumor progression in mice , 2011, BMC Immunology.

[89]  Karin Jirström,et al.  Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. , 2011, Cancer discovery.

[90]  S. Ricard-Blum.  The collagen family. , 2011, Cold Spring Harbor perspectives in biology.

[91]  P. De Baetselier,et al.  Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. , 2010, Cancer research.

[92]  Trey Ideker,et al.  A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates the B cell fate , 2010, Nature Immunology.

[93]  M. Robinson,et al.  A scaling normalization method for differential expression analysis of RNA-seq data , 2010, Genome Biology.

[94]  Mikala Egeblad,et al.  Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling , 2009, Cell.

[95]  Markus Nick,et al.  CheckMATE , 2018, Künstliche Intell..

[96]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[97]  Cynthia A. Reinhart-King,et al.  Tensional homeostasis and the malignant phenotype. , 2005, Cancer cell.

[98]  P. Sinha,et al.  Reduction of Myeloid-Derived Suppressor Cells and Induction of M1 Macrophages Facilitate the Rejection of Established Metastatic Disease1 , 2005, The Journal of Immunology.

[99]  J. Ochoa,et al.  l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes1 , 2003, The Journal of Immunology.

[100]  W. Durante,et al.  Transforming Growth Factor-&bgr;1 Stimulates l-Arginine Transport and Metabolism in Vascular Smooth Muscle Cells: Role in Polyamine and Collagen Synthesis , 2001, Circulation.

[101]  Kristi Kincaid,et al.  M-1/M-2 Macrophages and the Th1/Th2 Paradigm1 , 2000, The Journal of Immunology.

[102]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[103]  M. Caldwell,et al.  The temporal change in amino acid concentration within wound fluid--a putative rationale. , 1991, Progress in clinical and biological research.

[104]  A. Driessen,et al.  Regulation of arginine-ornithine exchange and the arginine deiminase pathway in Streptococcus lactis , 1987, Journal of bacteriology.

[105]  W. Falk,et al.  Suppression of cytotoxic T lymphocyte activation by L-ornithine. , 1985, Journal of immunology.