Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy.

The tumor microenvironment (TME) is an integral part of cancer. Recognition of the essential nature of the TME in cancer evolution has led to a shift from a tumor cell-centered view of cancer development to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. Accordingly, novel targets within the TME have been uncovered that can help direct and improve the actions of various cancer therapies, notably immunotherapies that work by potentiating host antitumor immune responses. Here, we review the composition of the TME, how this attenuates immunosurveillance, and discuss existing and potential strategies aimed at targeting cellular and molecular TME components.

[1]  Jedd D. Wolchok,et al.  PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations , 2016, Science Translational Medicine.

[2]  L. Galluzzi,et al.  First oncolytic virus approved for melanoma immunotherapy , 2016, Oncoimmunology.

[3]  S. Varambally,et al.  Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction , 2015, Nature Immunology.

[4]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[5]  Jason B. Williams,et al.  Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy , 2015, Science.

[6]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[7]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[8]  T. Gajewski,et al.  Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer , 2015, Clinical Cancer Research.

[9]  R. Schreiber,et al.  Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression , 2015, Cell.

[10]  Kathleen R. Cho,et al.  Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy , 2015, Nature.

[11]  D. Gabrilovich,et al.  Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. , 2015, The Journal of clinical investigation.

[12]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[13]  Dirk Schadendorf,et al.  Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. , 2015, The New England journal of medicine.

[14]  J. Weber,et al.  Immune checkpoint protein inhibition for cancer: preclinical justification for CTLA-4 and PD-1 blockade and new combinations. , 2015, Seminars in oncology.

[15]  Troy Guthrie,et al.  Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  T. Gajewski,et al.  Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity , 2015, Nature.

[17]  R. Motzer,et al.  Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[19]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[20]  Christopher J. Kane,et al.  Immunosuppressive plasma cells impede T cell-dependent immunogenic chemotherapy , 2015, Nature.

[21]  D. Schadendorf,et al.  Nivolumab in previously untreated melanoma without BRAF mutation. , 2015, The New England journal of medicine.

[22]  L. Zitvogel,et al.  Trial Watch: Peptide-based anticancer vaccines , 2015, Oncoimmunology.

[23]  C. Heirman,et al.  Targeting the tumor microenvironment to enhance antitumor immune responses , 2014, Oncotarget.

[24]  P. Hegde,et al.  MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer , 2014, Nature.

[25]  J. Kirkwood,et al.  Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. , 2014, JAMA.

[26]  M. Delorenzi,et al.  Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy , 2014, Nature Medicine.

[27]  J. Zavadil,et al.  Abstract 633: Inhibition of TGFβ as a strategy to convert the irradiated tumor into in situ individualized vaccine , 2014 .

[28]  D. Speiser,et al.  T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? , 2014, Nature Reviews Immunology.

[29]  Antoni Ribas,et al.  Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial , 2014, The Lancet.

[30]  M. Smyth,et al.  Targeting cancer-derived adenosine: new therapeutic approaches. , 2014, Cancer discovery.

[31]  Edward Y Kim,et al.  Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. , 2014, The Journal of clinical investigation.

[32]  C. Slingluff,et al.  Current status of granulocyte–macrophage colony-stimulating factor in the immunotherapy of melanoma , 2014, Journal of Immunotherapy for Cancer.

[33]  G. Coukos,et al.  Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors , 2014, Nature Medicine.

[34]  A. D. Van den Abbeele,et al.  Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma , 2014, Cancer Immunology Research.

[35]  H. Koblish,et al.  Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment , 2014, Journal of Immunotherapy for Cancer.

[36]  R. Weichselbaum,et al.  Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. , 2014, Cancer cell.

[37]  John D Lambris,et al.  The role of complement in tumor growth. , 2014, Advances in experimental medicine and biology.

[38]  H. Schreiber,et al.  Innate and adaptive immune cells in the tumor microenvironment , 2013, Nature Immunology.

[39]  J. Wolchok,et al.  Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma , 2013, The Journal of experimental medicine.

[40]  L. Zitvogel,et al.  Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. , 2013, Immunity.

[41]  C. Horak,et al.  Nivolumab plus ipilimumab in advanced melanoma. , 2013, The New England journal of medicine.

[42]  Antoni Ribas,et al.  Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. , 2013, The New England journal of medicine.

[43]  J. Wolchok,et al.  Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 , 2013, The Journal of experimental medicine.

[44]  G. Freeman,et al.  Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. , 2013, Cancer research.

[45]  A. Godkin,et al.  Home Sweet Home: The Tumor Microenvironment as a Haven for Regulatory T Cells , 2013, Front. Immunol..

[46]  Michael R. Green,et al.  Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. , 2013, The Journal of clinical investigation.

[47]  Huidong Shi,et al.  An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. , 2013, Immunity.

[48]  P. van Endert,et al.  Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. , 2013, Immunity.

[49]  Dai Fukumura,et al.  Vascular normalization as an emerging strategy to enhance cancer immunotherapy. , 2013, Cancer research.

[50]  Laurence Zitvogel,et al.  Immunogenic cell death in cancer therapy. , 2013, Annual review of immunology.

[51]  A. Palucka,et al.  Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet? , 2013, Science.

[52]  W. Wick,et al.  Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. , 2012, Cancer research.

[53]  R. Jain,et al.  Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy , 2012, Proceedings of the National Academy of Sciences.

[54]  V. Pascual,et al.  From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines , 2012, Nature Immunology.

[55]  G. Prendergast,et al.  IDO is a nodal pathogenic driver of lung cancer and metastasis development. , 2012, Cancer discovery.

[56]  A. Hauschild,et al.  Management of immune-related adverse events and kinetics of response with ipilimumab. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  E. Jaffee,et al.  Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. , 2012, Cancer research.

[58]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[59]  D. Matei,et al.  Abstract 3439: Tissue tranglutaminase (TG2) targeting by multifunctional field responsive gold nanoparticles , 2012 .

[60]  C. Sautès-Fridman,et al.  The immune contexture in human tumours: impact on clinical outcome , 2012, Nature Reviews Cancer.

[61]  R. Steinman.  Decisions about dendritic cells: past, present, and future. , 2012, Annual review of immunology.

[62]  Douglas Hanahan,et al.  Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment Prospects and Obstacles for Therapeutic Targeting of Function-enabling Stromal Cell Types , 2022 .

[63]  Y. Yonemitsu,et al.  Clinical and Immunologic Evaluation of Dendritic Cell–Based Immunotherapy in Combination With Gemcitabine and/or S-1 in Patients With Advanced Pancreatic Carcinoma , 2012, Pancreas.

[64]  Peter Vogel,et al.  Microenvironment and Immunology Immune Inhibitory Molecules Lag-3 and Pd-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape , 2022 .

[65]  E. Mardis,et al.  Cancer Exome Analysis Reveals a T Cell Dependent Mechanism of Cancer Immunoediting , 2012, Nature.

[66]  F. Di Virgilio,et al.  Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice , 2011, Science.

[67]  K. Murphy,et al.  Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells , 2011, The Journal of experimental medicine.

[68]  R. Schreiber,et al.  Type I interferon is selectively required by dendritic cells for immune rejection of tumors , 2011, The Journal of experimental medicine.

[69]  L. Lazzarato,et al.  Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells , 2011, The Journal of experimental medicine.

[70]  S. Pascolo,et al.  Gemcitabine depletes regulatory T‐cells in human and mice and enhances triggering of vaccine‐specific cytotoxic T‐cells , 2011, International journal of cancer.

[71]  G. Lesinski,et al.  Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. , 2011, Cancer research.

[72]  Axel Hoos,et al.  Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. , 2011, The New England journal of medicine.

[73]  B. Roschitzki,et al.  Abstract 5101: Biomarker identification in non-small cell lung cancer (NSCLC) with activity-based proteomics , 2011 .

[74]  R. Schreiber,et al.  Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion , 2011, Science.

[75]  L. Zitvogel,et al.  Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress , 2011, Oncogene.

[76]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[77]  R. Kerbel,et al.  Antiangiogenic therapy: impact on invasion, disease progression, and metastasis , 2011, Nature Reviews Clinical Oncology.

[78]  L. Bracci,et al.  Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. , 2011, Cancer research.

[79]  L. Zitvogel,et al.  Cyclophosphamide induces differentiation of Th17 cells in cancer patients. , 2011, Cancer research.

[80]  B. Nelson,et al.  CD20+ B Cells: The Other Tumor-Infiltrating Lymphocytes , 2010, The Journal of Immunology.

[81]  J. Kirkwood,et al.  Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients , 2010, The Journal of experimental medicine.

[82]  Jenna M. Sullivan,et al.  Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity , 2010, The Journal of experimental medicine.

[83]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[84]  S. Rosenberg,et al.  Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. , 2010, Cancer research.

[85]  Kohei Miyazono,et al.  TGFβ signalling: a complex web in cancer progression , 2010, Nature Reviews Cancer.

[86]  Y. DeClerck,et al.  Bone marrow-derived mesenchymal stem cells and the tumor microenvironment , 2010, Cancer and Metastasis Reviews.

[87]  J. Vincent,et al.  5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. , 2010, Cancer research.

[88]  Z. Werb,et al.  Matrix Metalloproteinases: Regulators of the Tumor Microenvironment , 2010, Cell.

[89]  J. Allison,et al.  PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors , 2010, Proceedings of the National Academy of Sciences.

[90]  A. Dalgleish,et al.  Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses , 2009, British Journal of Cancer.

[91]  S. Kim-Schulze,et al.  Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma , 2010, Annals of Surgical Oncology.

[92]  Steven Piantadosi,et al.  Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[93]  K. Harrington,et al.  Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[94]  J. Tschopp,et al.  Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors , 2009, Nature Medicine.

[95]  L. Coussens,et al.  CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. , 2009, Cancer cell.

[96]  Y. Hirooka,et al.  A Combination Therapy of Gemcitabine With Immunotherapy for Patients With Inoperable Locally Advanced Pancreatic Cancer , 2009, Pancreas.

[97]  J. Pollard,et al.  Microenvironmental regulation of metastasis , 2009, Nature Reviews Cancer.

[98]  S. Qiu,et al.  Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma , 2009, Clinical Cancer Research.

[99]  D. Foell,et al.  Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells1 , 2008, The Journal of Immunology.

[100]  W. Nacken,et al.  Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein , 2008, The Journal of experimental medicine.

[101]  C. Hawrylowicz,et al.  Strategies for use of IL‐10 or its antagonists in human disease , 2008, Immunological reviews.

[102]  Fabian Kiessling,et al.  Vascular normalization in Rgs5-deficient tumours promotes immune destruction , 2008, Nature.

[103]  Dong Wei,et al.  Phase I Clinical Trial of Autologous Ascites-derived Exosomes Combined With GM-CSF for Colorectal Cancer , 2008, Molecular Therapy.

[104]  J. Leips,et al.  Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. , 2007, Cancer research.

[105]  Laurence Zitvogel,et al.  Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy , 2007, Nature Medicine.

[106]  C. Aspord,et al.  Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development , 2007, The Journal of experimental medicine.

[107]  P. Sinha,et al.  Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. , 2007, Cancer research.

[108]  G. Freeman,et al.  The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection , 2007, Nature Immunology.

[109]  M. Sporn,et al.  The tumour microenvironment as a target for chemoprevention , 2007, Nature Reviews Cancer.

[110]  W. Gillanders,et al.  Defining the Ability of Cyclophosphamide Preconditioning to Enhance the Antigen-specific CD8+ T-cell Response to Peptide Vaccination: Creation of a Beneficial Host Microenvironment Involving Type I IFNs and Myeloid Cells , 2007, Journal of immunotherapy.

[111]  L. Zitvogel,et al.  Calreticulin exposure dictates the immunogenicity of cancer cell death , 2007, Nature Medicine.

[112]  B. Chauffert,et al.  Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients , 2007, Cancer Immunology, Immunotherapy.

[113]  K. Mills,et al.  Suppression of Antitumor Immunity by IL-10 and TGF-β-Producing T Cells Infiltrating the Growing Tumor: Influence of Tumor Environment on the Induction of CD4+ and CD8+ Regulatory T Cells1 , 2006, The Journal of Immunology.

[114]  G. Freeman,et al.  Restoring function in exhausted CD8 T cells during chronic viral infection , 2006, Nature.

[115]  J. Leips,et al.  Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression1 , 2006, The Journal of Immunology.

[116]  L. Coussens,et al.  Paradoxical roles of the immune system during cancer development , 2006, Nature Reviews Cancer.

[117]  E. Jaffee,et al.  Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response , 2005, The Journal of experimental medicine.

[118]  J. Schlom,et al.  Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. , 2005, Blood.

[119]  B. Chauffert,et al.  CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative , 2004, European journal of immunology.

[120]  J. Frelinger,et al.  Induction of Tumor Cell Apoptosis In Vivo Increases Tumor Antigen Cross-Presentation, Cross-Priming Rather than Cross-Tolerizing Host Tumor-Specific CD8 T Cells1 , 2003, The Journal of Immunology.

[121]  Haidong Dong,et al.  Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion , 2002, Nature Medicine.

[122]  Charles A. Janeway,et al.  Decoding the Patterns of Self and Nonself by the Innate Immune System , 2002, Science.

[123]  C. Janeway,et al.  Innate immune recognition. , 2002, Annual review of immunology.

[124]  D. Carbone,et al.  Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells , 1996, Nature Medicine.

[125]  J. Fagerberg.  Granulocyte-macrophage colony-stimulating factor as an adjuvant in tumor immunotherapy. , 1996, Medical oncology.

[126]  D. Parker.  T cell-dependent B cell activation. , 1993, Annual review of immunology.