Home LiteratureArticle Details
PMID: 29686425 Published · ppublish English Journal Article Review

Understanding the tumor immune microenvironment (TIME) for effective therapy.

Nature medicine ·Vol. 24 ·No. 5 ·2018-00-00 ·Pages 541-550

Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF

Abstract

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

MeSH Terms
Genotype Humans Immunotherapy Neoplasm Metastasis Neoplasms/genetics,immunology,pathology Phenotype Tumor Microenvironment/immunology
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Binnewies Mikhail
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Roberts Edward W
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Kersten Kelly
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Chan Vincent ORCID
UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA, USA.
Fearon Douglas F
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Merad Miriam
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Coussens Lisa M
Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, USA.
Gabrilovich Dmitry I
The Wistar Institute, Philadelphia, PA, USA.
Ostrand-Rosenberg Suzanne ORCID
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA. | Huntsman Cancer Institute and Department of Pathology, University of Utah, Salt Lake City, UT, USA.
Hedrick Catherine C
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
Vonderheide Robert H
Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Pittet Mikael J
Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
Jain Rakesh K
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Zou Weiping
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Howcroft T Kevin
Division of Cancer Biology, NCI, NIH, Bethesda, MD, USA.
Woodhouse Elisa C
Division of Cancer Biology, NCI, NIH, Bethesda, MD, USA.
Weinberg Robert A
Whitehead Institute for Biomedical Research, Cambridge, MA, USA. [email protected].
Krummel Matthew F ORCID
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. [email protected]. | UCSF Immunoprofiler Initiative, University of California, San Francisco, San Francisco, CA, USA. [email protected].
References (111)
111 references, click to expand
  1. Immune checkpoint blockade: a common denominator approach to cancer therapy.
    Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015). PMID: 25858804
  2. Patterns of Immune Infiltration in Breast Cancer and Their Clinical Implications: A Gene-Expression-Based Retrospective Study.
    Ali, H. R., Chlon, L., Pharoah, P. D., Markowetz, F. & Caldas, C. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med. 13, e1002194 (2016). PMID: 27959923
  3. Robust enumeration of cell subsets from tissue expression profiles.
    Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015). PMID: 25822800
  4. xCell: digitally portraying the tissue cellular heterogeneity landscape.
    Aran, D., Hu, Z. & Butte, A. J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 18, 220 (2017). PMID: 29141660
  5. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.
    Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013). PMID: 24138885
  6. Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability.
    Mlecnik, B. et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44, 698–711 (2016). PMID: 26982367
  7. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
    Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014). PMID: 25428504
  8. Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+CD18+ cells and CD8+CD103+ cells by multi-epitope imaging.
    Ademmer, K. et al. Effector T lymphocyte subsets in human pancreatic cancer: detection of CD8+CD18+ cells and CD8+CD103+ cells by multi-epitope imaging. Clin. Exp. Immunol. 112, 21–26 (1998). PMID: 9566785
  9. Exclusion of T Cells From Pancreatic Carcinomas in Mice Is Regulated by Ly6C(low) F4/80(+) Extratumoral Macrophages.
    Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 149, 201–210 (2015). PMID: 25888329
  10. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment.
    Spranger, S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int. Immunol. 28, 383–391 (2016). PMID: 26989092
  11. Evans, R. A. et al. Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI Insight 1, e88328 (2016).
  12. Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer.
    Lee, H. J. et al. Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J. Clin. Pathol. 69, 422–430 (2016). PMID: 26475777
  13. Tertiary Lymphoid Structures in Cancers: Prognostic Value, Regulation, and Manipulation for Therapeutic Intervention.
    Sautès-Fridman, C. et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front. Immunol. 7, 407 (2016). PMID: 27752258
  14. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.
    Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015). PMID: 26502405
  15. Tertiary lymphoid organs in infection and autoimmunity.
    Neyt, K., Perros, F., GeurtsvanKessel, C. H., Hammad, H. & Lambrecht, B. N. Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33, 297–305 (2012). PMID: 22622061
  16. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation.
    Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014). PMID: 24942756
  17. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells.
    Sumimoto, H., Imabayashi, F., Iwata, T. & Kawakami, Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J. Exp. Med. 203, 1651–1656 (2006). PMID: 16801397
  18. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.
    Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012). PMID: 22698407
  19. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer.
    Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012). PMID: 22698406
  20. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity.
    Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014). PMID: 25446897
  21. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy.
    Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e714 (2017). PMID: 28486109
  22. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
    Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015). PMID: 25970248
  23. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis.
    Qian, B.-Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). PMID: 21654748
  24. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer.
    Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015). PMID: 25679762
  25. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.
    Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006). PMID: 16439202
  26. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy.
    Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001). PMID: 11257139
  27. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis.
    Scholl, S. M. et al. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J. Natl. Cancer Inst. 86, 120–126 (1994). PMID: 8271294
  28. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.
    DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009). PMID: 19647220
  29. Tumour-educated macrophages promote tumour progression and metastasis.
    Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004). PMID: 14708027
  30. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma.
    Khalili, J. S. et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin. Cancer Res. 18, 5329–5340 (2012). PMID: 22850568
  31. Non-cell-autonomous tumor suppression by p53.
    Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013). PMID: 23562644
  32. The consensus molecular subtypes of colorectal cancer.
    Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015). PMID: 26457759
  33. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy.
    Angelova, M. et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015). PMID: 25853550
  34. Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy.
    Becht, E. et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22, 4057–4066 (2016). PMID: 26994146
  35. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type.
    Gatalica, Z. et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol. Biomarkers Prev. 23, 2965–2970 (2014). PMID: 25392179
  36. Boland, P. M. & Ma, W. W. Immunotherapy for colorectal cancer. Cancers (Basel) 9, E50 (2017).
  37. Tumors as organs: complex tissues that interface with the entire organism.
    Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010). PMID: 20627072
  38. Microenvironmental regulation of tumor progression and metastasis.
    Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013). PMID: 24202395
  39. Immune cell promotion of metastasis.
    Kitamura, T., Qian, B.-Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015). PMID: 25614318
  40. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance.
    Willimsky, G. & Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005). PMID: 16136144
  41. Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses.
    Garbe, A. I. et al. Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses. Cancer Res. 66, 508–516 (2006). PMID: 16397267
  42. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression.
    DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011). PMID: 21251614
  43. Overcoming T cell exhaustion in infection and cancer.
    Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015). PMID: 25797516
  44. T cell exhaustion.
    Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011). PMID: 21739672
  45. Chromatin states define tumour-specific T cell dysfunction and reprogramming.
    Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017). PMID: 28514453
  46. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.
    Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016). PMID: 27789795
  47. Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.
    Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016). PMID: 27521269
  48. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.
    Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014). PMID: 25446896
  49. Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.
    Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017). PMID: 29136508
  50. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy.
    Bos, P. D., Plitas, G., Rudra, D., Lee, S. Y. & Rudensky, A. Y. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J. Exp. Med. 210, 2435–2466 (2013). PMID: 24127486
  51. Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression.
    Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338.e6 (2017). PMID: 28813661
  52. The cellular and molecular origin of tumor-associated macrophages.
    Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014). PMID: 24812208
  53. Macrophage activation and polarization: nomenclature and experimental guidelines.
    Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014). PMID: 25035950
  54. The chemokine system in diverse forms of macrophage activation and polarization.
    Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004). PMID: 15530839
  55. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).
  56. Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
    Gunderson, A. J. et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6, 270–285 (2016). PMID: 26715645
  57. PI3Kγ is a molecular switch that controls immune suppression.
    Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016). PMID: 27642729
  58. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.
    Daley, D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23, 556–567 (2017). PMID: 28394331
  59. Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma.
    Roberts, E. W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016). PMID: 27424807
  60. Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.
    Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016). PMID: 27096321
  61. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.
    Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008). PMID: 19008445
  62. Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells.
    Sánchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov 6, 71–79 (2016). PMID: 26493961
  63. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis.
    Qian, B.-Z. et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J. Exp. Med. 212, 1433–1448 (2015). PMID: 26261265
  64. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.
    Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015). PMID: 26056232
  65. Visualization of immediate immune responses to pioneer metastatic cells in the lung.
    Headley, M. B. et al. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531, 513–517 (2016). PMID: 26982733
  66. Patrolling monocytes control tumor metastasis to the lung.
    Hanna, R. N. et al. Patrolling monocytes control tumor metastasis to the lung. Science 350, 985–990 (2015). PMID: 26494174
  67. Neutrophils support lung colonization of metastasis-initiating breast cancer cells.
    Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015). PMID: 26649828
  68. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.
    Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016). PMID: 27055731
  69. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.
    Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015). PMID: 25822788
  70. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils.
    Casbon, A.-J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. USA 112, E566–E575 (2015). PMID: 25624500
  71. Tumor entrained neutrophils inhibit seeding in the premetastatic lung.
    Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011). PMID: 21907922
  72. MET is required for the recruitment of anti-tumoural neutrophils.
    Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015). PMID: 25985180
  73. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma.
    Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016). PMID: 27265504
  74. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes.
    Kowanetz, M. et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl. Acad. Sci. USA 107, 21248–21255 (2010). PMID: 21081700
  75. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis.
    Jamieson, T. et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Invest. 122, 3127–3144 (2012). PMID: 22922255
  76. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma.
    Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014). PMID: 24572365
  77. Exercise-dependent regulation of the tumour microenvironment.
    Koelwyn, G. J., Quail, D. F., Zhang, X., White, R. M. & Jones, L. W. Exercise-dependent regulation of the tumour microenvironment. Nat. Rev. Cancer 17, 620–632 (2017). PMID: 28943640
  78. Age-dependent dysregulation of innate immunity.
    Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013). PMID: 24157572
  79. The impact of diet on asthma and allergic diseases.
    Julia, V., Macia, L. & Dombrowicz, D. The impact of diet on asthma and allergic diseases. Nat. Rev. Immunol. 15, 308–322 (2015). PMID: 25907459
  80. Cholesterol, inflammation and innate immunity.
    Tall, A. R. & Yvan-Charvet, L. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol. 15, 104–116 (2015). PMID: 25614320
  81. Interactions between the microbiota and the immune system.
    Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012). PMID: 22674334
  82. Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses.
    Robinson, D. P., Lorenzo, M. E., Jian, W. & Klein, S. L. Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses. PLoS Pathog. 7, e1002149 (2011). PMID: 21829352
  83. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.
    Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017). PMID: 28855077
  84. Cook, N. R. et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. J. Am. Med. Assoc. 294, 47–55 (2005).
  85. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.
    Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011). PMID: 22036019
  86. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity.
    Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015). PMID: 26343581
  87. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor.
    Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32, 790–802 (2010). PMID: 20605485
  88. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism.
    Waight, J. D., Hu, Q., Miller, A., Liu, S. & Abrams, S. I. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One 6, e27690 (2011). PMID: 22110722
  89. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils.
    Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358, eaal5081 (2017). PMID: 29191879
  90. Angiotensin II drives the production of tumor-promoting macrophages.
    Cortez-Retamozo, V. et al. Angiotensin II drives the production of tumor-promoting macrophages. Immunity 38, 296–308 (2013). PMID: 23333075
  91. PF4 Promotes Platelet Production and Lung Cancer Growth.
    Pucci, F. et al. PF4 promotes platelet production and lung cancer growth. Cell Rep. 17, 1764–1772 (2016). PMID: 27829148
  92. Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer.
    Verschoor, C. P. et al. Blood CD33+HLA-DR– myeloid-derived suppressor cells are increased with age and a history of cancer. J. Leukoc. Biol. 93, 633–637 (2013). PMID: 23341539
  93. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.
    Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016). PMID: 27272654
  94. Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2.
    Hale, M. et al. Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2. PLoS One 10, e0118784 (2015). PMID: 25769110
  95. Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells.
    Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov 7, 72–85 (2017). PMID: 27694385
  96. FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice.
    Thompson, M. G., Peiffer, D. S., Larson, M., Navarro, F. & Watkins, S. K. FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice. Cancer Immunol. Immunother. 66, 615–625 (2017). PMID: 28229217
  97. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.
    Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015). PMID: 26541606
  98. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.
    Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015). PMID: 26541610
  99. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature.
    Kokolus, K. M. et al. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proc. Natl. Acad. Sci. USA 110, 20176–20181 (2013). PMID: 24248371
  100. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice.
    Kokolus, K. M. et al. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice. Front. Immunol. 5, 23 (2014). PMID: 24575090
  101. Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity.
    Flint, T. R. et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016). PMID: 27829137
  102. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance.
    Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016). PMID: 27411589
  103. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity.
    Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016). PMID: 27411588
  104. Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation.
    Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 (2016). e1512. PMID: 27610573
  105. Combination cancer immunotherapies tailored to the tumour microenvironment.
    Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143–158 (2016). PMID: 26598942
  106. Quantitative Multiplex Immunohistochemistry Reveals Myeloid-Inflamed Tumor-Immune Complexity Associated with Poor Prognosis.
    Tsujikawa, T. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep. 19, 203–217 (2017). PMID: 28380359
  107. Systemic Immunity Is Required for Effective Cancer Immunotherapy.
    Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502.e15 (2017). PMID: 28111070
  108. Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses.
    Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765.e17 (2017). PMID: 28475900
  109. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
    Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016). PMID: 27124452
  110. Multiplex genome engineering using CRISPR/Cas systems.
    Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013). PMID: 23287718
  111. Patient-centered community pharmacy: a mirage.
    Wang, H. et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153, 910–918 (2013). PMID: 3969854
Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/s41591-018-0014-x
Email
[email protected]
[email protected]
Published
2018-00-00
Epub
2018-00-23
Pages
541-550
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC5998822
Subset
IM
Grants
NCI NIH HHS · R35 CA197743 · United States
NCI NIH HHS · R01 CA202987 · United States
NCI NIH HHS · P01 CA080124 · United States
NCI NIH HHS · R01 CA211016 · United States
NCI NIH HHS · R01 CA208205 · United States
NCI NIH HHS · R01 CA206890 · United States
NICHD NIH HHS · T32 HD007470 · United States
NCI NIH HHS · R01 CA173861 · United States
NIAID NIH HHS · R01 AI114787 · United States
NCI NIH HHS · P30 CA010815 · United States
NCI NIH HHS · R01 CA190400 · United States
External Links
PubMed source DOI: 10.1038/s41591-018-0014-x PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2