Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy

Cancer immunotherapies that harness the body's immune system to combat tumors have received extensive attention and become mainstream strategies for treating cancer. Despite promising results, some problems remain, such as the limited patient response rate and the emergence of severe immune‐related adverse effects. For most patients, the therapeutic efficacy of cancer immunotherapy is mainly limited by the immunosuppressive tumor microenvironment (TME). To overcome such obstacles in the TME, the immunomodulation of immunosuppressive factors and therapeutic immune cells (e.g., T cells and antigen‐presenting cells) should be carefully designed and evaluated. Nanoengineered synthetic immune niches have emerged as highly customizable platforms with a potent capability for reprogramming the immunosuppressive TME. Here, recent developments in nano‐biomaterials that are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy which are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy are highlighted.

[1]  Soong Ho Um,et al.  Implantable Synthetic Immune Niche for Spatiotemporal Modulation of Tumor‐Derived Immunosuppression and Systemic Antitumor Immunity: Postoperative Immunotherapy , 2018, Advanced materials.

[2]  Tingting Meng,et al.  Inhibition of tumor-promoting stroma to enforce subsequently targeting AT1R on tumor cells by pathological inspired micelles. , 2018, Biomaterials.

[3]  Jedd D. Wolchok,et al.  Cancer immunotherapy using checkpoint blockade , 2018, Science.

[4]  Omkar U. Kawalekar,et al.  CAR T cell immunotherapy for human cancer , 2018, Science.

[5]  Zhuang Liu,et al.  Tumor vasculature normalization by orally fed erlotinib to modulate the tumor microenvironment for enhanced cancer nanomedicine and immunotherapy. , 2017, Biomaterials.

[6]  M. Ferrari,et al.  Enhancing cancer immunotherapy through nanotechnology-mediated tumor infiltration and activation of immune cells. , 2017, Seminars in immunology.

[7]  A. Nel,et al.  Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression , 2017, Nature Communications.

[8]  J. Hubbell,et al.  Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events , 2017, Science Translational Medicine.

[9]  Zhuang Liu,et al.  Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses , 2017, Nature Communications.

[10]  Q. Luo,et al.  Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages. , 2017, ACS nano.

[11]  Zhiping Zhang,et al.  Tumor Microenvironment Responsive Nanogel for the Combinatorial Antitumor Effect of Chemotherapy and Immunotherapy. , 2017, Nano letters.

[12]  C. Figdor,et al.  Synthetic immune niches for cancer immunotherapy , 2017, Nature Reviews Immunology.

[13]  S. Shen,et al.  Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice , 2017, Scientific Reports.

[14]  Leaf Huang,et al.  Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer. , 2017, ACS nano.

[15]  Quanyin Hu,et al.  Tailoring Biomaterials for Cancer Immunotherapy: Emerging Trends and Future Outlook , 2017, Advanced materials.

[16]  Sudha Rao,et al.  Epigenetics and immunotherapy: The current state of play , 2017, Molecular immunology.

[17]  John-William Sidhom,et al.  Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth. , 2017, ACS nano.

[18]  Tian Zhang,et al.  Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy , 2017, Nature Nanotechnology.

[19]  Song Shen,et al.  Spatial Targeting of Tumor-Associated Macrophages and Tumor Cells with a pH-Sensitive Cluster Nanocarrier for Cancer Chemoimmunotherapy. , 2017, Nano letters.

[20]  D. Irvine,et al.  Delivering safer immunotherapies for cancer , 2017, Advanced drug delivery reviews.

[21]  N. Erez,et al.  Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1 , 2017, Oncogene.

[22]  J. Wargo,et al.  Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy , 2017, Cell.

[23]  Z. Johnson,et al.  Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  Yadong Wang,et al.  Localized Multi‐Component Delivery Platform Generates Local and Systemic Anti‐Tumor Immunity , 2017 .

[25]  William Y. Kim,et al.  Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors. , 2017, Cancer research.

[26]  Soong Ho Um,et al.  Multifaceted Immunomodulatory Nanoliposomes: Reshaping Tumors into Vaccines for Enhanced Cancer Immunotherapy , 2017 .

[27]  Zhen Gu,et al.  In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy , 2017, Nature Biomedical Engineering.

[28]  Yuhua Wang,et al.  Tumor‐targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[29]  J. Moon,et al.  Designer vaccine nanodiscs for personalized cancer immunotherapy , 2016, Nature materials.

[30]  Yichao Chen,et al.  An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy , 2016, Nature Communications.

[31]  Morteza Mahmoudi,et al.  Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. , 2016, Nature nanotechnology.

[32]  M. Branca Rekindling cancer vaccines , 2016, Nature Biotechnology.

[33]  M. Milowsky,et al.  The Binding Site Barrier Elicited by Tumor-Associated Fibroblasts Interferes Disposition of Nanoparticles in Stroma-Vessel Type Tumors. , 2016, ACS nano.

[34]  Quanyin Hu,et al.  Synergistic Transcutaneous Immunotherapy Enhances Antitumor Immune Responses through Delivery of Checkpoint Inhibitors. , 2016, ACS nano.

[35]  K. Leong,et al.  Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy. , 2016, Biomaterials.

[36]  A. Jebali,et al.  The inhibition of epidermal growth factor receptor signaling by hexagonal selenium nanoparticles modified by SiRNA , 2016, Cancer Gene Therapy.

[37]  P. Choyke,et al.  Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy , 2016, Science Translational Medicine.

[38]  Matthieu Texier,et al.  Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination , 2016, Nature Reviews Clinical Oncology.

[39]  A. Italiano,et al.  Molecular Pathways: Immune Checkpoint Antibodies and their Toxicities , 2016, Clinical Cancer Research.

[40]  J. Benoit,et al.  Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy. , 2016, Biomaterials.

[41]  Jun Wang,et al.  Restoring anti-tumor functions of T cells via nanoparticle-mediated immune checkpoint modulation. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[42]  Renier J. Brentjens,et al.  Driving CAR T-cells forward , 2016, Nature Reviews Clinical Oncology.

[43]  Özlem Türeci,et al.  Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy , 2016, Nature.

[44]  R. Bourgon,et al.  Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial , 2016, The Lancet.

[45]  F. Hodi,et al.  Talimogene Laherparepvec for the Treatment of Advanced Melanoma , 2016, Clinical Cancer Research.

[46]  M. Koch,et al.  Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. , 2016, Cancer cell.

[47]  P. Keegan,et al.  FDA Approval Summary: Pembrolizumab for the Treatment of Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Express Programmed Death-Ligand 1 , 2016, The oncologist.

[48]  Zhen Gu,et al.  Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody. , 2016, Nano letters.

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

[50]  Roger D Kamm,et al.  Impact of the physical microenvironment on tumor progression and metastasis. , 2016, Current opinion in biotechnology.

[51]  Gang Zheng,et al.  Tailoring nanoparticle designs to target cancer based on tumor pathophysiology , 2016, Proceedings of the National Academy of Sciences.

[52]  Gang Wu,et al.  Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity , 2016, Oncoimmunology.

[53]  J. Soria,et al.  Immune-related adverse events with immune checkpoint blockade: a comprehensive review. , 2016, European journal of cancer.

[54]  Jia Hua Cheng,et al.  Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation , 2016, Oncogenesis.

[55]  Yuhua Wang,et al.  Nanoparticle delivery of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma. , 2015, Biomaterials.

[56]  Michael Y. Gerner,et al.  In vivo characterization of the physicochemical properties of TLR agonist delivery that enhance vaccine immunogenicity , 2015, Nature Biotechnology.

[57]  Erik Sahai,et al.  Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity , 2015, Cell.

[58]  I. Melero,et al.  Evolving synergistic combinations of targeted immunotherapies to combat cancer , 2015, Nature Reviews Cancer.

[59]  S. Rokudai,et al.  Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma , 2015, Cancer Immunology, Immunotherapy.

[60]  H. Byrne,et al.  Dual Targeted Immunotherapy via In Vivo Delivery of Biohybrid RNAi‐Peptide Nanoparticles to Tumor‐Associated Macrophages and Cancer Cells , 2015, Advanced functional materials.

[61]  K. Kinzler,et al.  Enrichment and Expansion with Nanoscale Artificial Antigen Presenting Cells for Adoptive Immunotherapy. , 2015, ACS nano.

[62]  M. Atkins,et al.  Toxicities of Immunotherapy for the Practitioner. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  D. Irvine,et al.  Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells , 2015, Science Translational Medicine.

[64]  J. Hubbell,et al.  6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice , 2015, Cancer Immunology, Immunotherapy.

[65]  L. Galluzzi,et al.  Combinatorial Strategies for the Induction of Immunogenic Cell Death , 2015, Front. Immunol..

[66]  Michael S. Goldberg,et al.  Immunoengineering: How Nanotechnology Can Enhance Cancer Immunotherapy , 2015, Cell.

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

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

[69]  C. Sheridan IDO inhibitors move center stage in immuno-oncology , 2015, Nature Biotechnology.

[70]  J. Lang,et al.  Augmenting Antitumor Immune Responses with Epigenetic Modifying Agents , 2015, Front. Immunol..

[71]  Yang Yang,et al.  Nanoparticle-based immunotherapy for cancer. , 2015, ACS nano.

[72]  A. Salem,et al.  Three Steps to Breaking Immune Tolerance to Lymphoma: A Microparticle Approach , 2015, Cancer Immunology Research.

[73]  Youngjin Choi,et al.  Injectable, spontaneously assembling inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy , 2014, Nature Biotechnology.

[74]  Junfeng Zhang,et al.  Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy. , 2014, Biomaterials.

[75]  Ligeng Xu,et al.  Immunological Responses Triggered by Photothermal Therapy with Carbon Nanotubes in Combination with Anti‐CTLA‐4 Therapy to Inhibit Cancer Metastasis , 2014, Advanced materials.

[76]  S. B. Stephan,et al.  Biopolymer implants enhance the efficacy of adoptive T cell therapy , 2014, Nature Biotechnology.

[77]  F. Osorio,et al.  Tumor cell lysates as immunogenic sources for cancer vaccine design , 2014, Human vaccines & immunotherapeutics.

[78]  Tarek R. Fadel,et al.  A carbon nanotube-polymer composite for T-cell therapy. , 2014, Nature nanotechnology.

[79]  Nimit L. Patel,et al.  COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models , 2014, Science Translational Medicine.

[80]  J. Blay,et al.  Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. , 2014, Cancer cell.

[81]  M. Maio,et al.  Epigenetic drugs as immunomodulators for combination therapies in solid tumors. , 2014, Pharmacology & therapeutics.

[82]  Yuan Zhang,et al.  Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[83]  A. Yu,et al.  Enhancement of all-trans retinoic acid-induced differentiation by pH-sensitive nanoparticles for solid tumor cells. , 2014, Macromolecular bioscience.

[84]  Yuhua Wang,et al.  Nanoparticle-Delivered Transforming Growth Factor-β siRNA Enhances Vaccination against Advanced Melanoma by Modifying Tumor Microenvironment , 2014, ACS nano.

[85]  S. Riddell,et al.  Design and implementation of adoptive therapy with chimeric antigen receptor‐modified T cells , 2014, Immunological reviews.

[86]  Jennifer Couzin-Frankel,et al.  Breakthrough of the year 2013. Cancer immunotherapy. , 2013, Science.

[87]  S. Bhattacharyya,et al.  FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. , 2013, Immunity.

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

[89]  S. Pun,et al.  Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival , 2013, Proceedings of the National Academy of Sciences.

[90]  Shyh-Dar Li,et al.  Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. , 2013, Cancer research.

[91]  P. Darcy,et al.  Gene-engineered T cells for cancer therapy , 2013, Nature Reviews Cancer.

[92]  C. Melief,et al.  Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell–Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects , 2013, Clinical Cancer Research.

[93]  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.

[94]  Nunzio Bottini,et al.  In vivo targeting of intratumor regulatory T cells using PEG-modified single-walled carbon nanotubes. , 2013, Bioconjugate chemistry.

[95]  Lili Li,et al.  Lipid-polymer nanoparticles encapsulating doxorubicin and 2'-deoxy-5-azacytidine enhance the sensitivity of cancer cells to chemical therapeutics. , 2013, Molecular pharmaceutics.

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

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

[98]  J. Benoit,et al.  Gemcitabine versus Modified Gemcitabine: a review of several promising chemical modifications. , 2013, Molecular pharmaceutics.

[99]  Pieter Wesseling,et al.  The immunosuppressive tumour network: myeloid‐derived suppressor cells, regulatory T cells and natural killer T cells , 2013, Immunology.

[100]  Z. Hou,et al.  Delivery of ursolic acid (UA) in polymeric nanoparticles effectively promotes the apoptosis of gastric cancer cells through enhanced inhibition of cyclooxygenase 2 (COX-2). , 2013, International journal of pharmaceutics.

[101]  Sunil Singhal,et al.  Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery , 2012, Proceedings of the National Academy of Sciences.

[102]  Anirban Sen Gupta,et al.  EGF receptor-targeted nanocarriers for enhanced cancer treatment. , 2012, Nanomedicine.

[103]  N. Davies,et al.  Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)-b-poly(DL-lactic acid) micelle nanocarriers: characterization and effects on pharmacokinetics in rat serum and urine. , 2012, Journal of pharmaceutical sciences.

[104]  Richard A Flavell,et al.  Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. , 2012, Nature materials.

[105]  D. Irvine,et al.  Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles. , 2012, Biomaterials.

[106]  C. Gong,et al.  Biodegradable Thermosensitive Hydrogel for SAHA and DDP Delivery: Therapeutic Effects on Oral Squamous Cell Carcinoma Xenografts , 2012, PloS one.

[107]  Steven A. Rosenberg,et al.  Adoptive immunotherapy for cancer: harnessing the T cell response , 2012, Nature Reviews Immunology.

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

[109]  Junfeng Zhang,et al.  Targeted delivery of oligonucleotides into tumor-associated macrophages for cancer immunotherapy. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[110]  Z. Werb,et al.  The extracellular matrix: A dynamic niche in cancer progression , 2012, The Journal of cell biology.

[111]  Jinho Park,et al.  Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy , 2012, Theranostics.

[112]  P. Kalinski Regulation of Immune Responses by Prostaglandin E2 , 2012, The Journal of Immunology.

[113]  George Coukos,et al.  Cancer immunotherapy comes of age , 2011, Nature.

[114]  P. Pauwels,et al.  Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy , 2011, Clinical & developmental immunology.

[115]  I. Štěpánek,et al.  Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status , 2011, British Journal of Cancer.

[116]  I. Holen,et al.  Tumour macrophages as potential targets of bisphosphonates , 2011, Journal of Translational Medicine.

[117]  Jinghang Zhang,et al.  CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis , 2011, Nature.

[118]  P. Fisher,et al.  The potential of celecoxib-loaded hydroxyapatite-chitosan nanocomposite for the treatment of colon cancer. , 2011, Biomaterials.

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

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

[121]  Kati Räsänen,et al.  Activation of fibroblasts in cancer stroma. , 2010, Experimental cell research.

[122]  Peter A. Jones,et al.  Epigenetic Modifications as Therapeutic Targets , 2010, Nature Biotechnology.

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

[124]  Jun Liu,et al.  Local release of highly loaded antibodies from functionalized nanoporous support for cancer immunotherapy. , 2010, Journal of the American Chemical Society.

[125]  Kristian Pietras,et al.  Hallmarks of cancer: interactions with the tumor stroma. , 2010, Experimental cell research.

[126]  David J Mooney,et al.  In Situ Regulation of DC Subsets and T Cells Mediates Tumor Regression in Mice , 2009, Science Translational Medicine.

[127]  A. Lavasanifar,et al.  Immunomodulatory and anticancer effects of intra-tumoral co-delivery of synthetic lipid A adjuvant and STAT3 inhibitor, JSI-124 , 2009, Immunopharmacology and immunotoxicology.

[128]  K. Scharffetter-Kochanek,et al.  Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis. , 2009, The Journal of investigative dermatology.

[129]  R. Figlin,et al.  Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. , 2009, Cancer research.

[130]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[131]  Heather R. Roberts,et al.  The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. , 2009, Carcinogenesis.

[132]  David J. Mooney,et al.  Infection-Mimicking Materials to Program Dendritic Cells In Situ , 2008, Nature materials.

[133]  P. Dahm,et al.  Reversal of Myeloid Cell–Mediated Immunosuppression in Patients with Metastatic Renal Cell Carcinoma , 2008, Clinical Cancer Research.

[134]  J. Massagué,et al.  TGFβ in Cancer , 2008, Cell.

[135]  D. Vignali,et al.  How regulatory T cells work , 2008, Nature Reviews Immunology.

[136]  Katrin Schwarz,et al.  Nanoparticles target distinct dendritic cell populations according to their size , 2008, European journal of immunology.

[137]  S. Breslin Cytokine-release syndrome: overview and nursing implications. , 2007, Clinical journal of oncology nursing.

[138]  Sai T Reddy,et al.  Exploiting lymphatic transport and complement activation in nanoparticle vaccines , 2007, Nature Biotechnology.

[139]  Y. Wan,et al.  Transforming Growth Factor-β and the Immune Response: Implications for Anticancer Therapy , 2007, Clinical Cancer Research.

[140]  A. Mantovani,et al.  Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. , 2007, The Journal of investigative dermatology.

[141]  R. Akhurst,et al.  TGF beta inhibition for cancer therapy. , 2006, Current cancer drug targets.

[142]  C. Blank,et al.  Immune resistance orchestrated by the tumor microenvironment , 2006, Immunological reviews.

[143]  Kelly B. Moran,et al.  Phase I Trial of Sequential Low-Dose 5-Aza-2′-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma , 2006, Clinical Cancer Research.

[144]  R. Schwendener,et al.  Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach , 2006, British Journal of Cancer.

[145]  A. Karpf A Potential Role for Epigenetic Modulatory Drugs in the Enhancement of Cancer/Germ-Line Antigen Vaccine Efficacy , 2006, Epigenetics.

[146]  T. Tomasi,et al.  Epigenetic regulation of immune escape genes in cancer , 2006, Cancer Immunology, Immunotherapy.

[147]  John Condeelis,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[148]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[149]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[150]  C. Uyttenhove,et al.  Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase , 2003, Nature Medicine.

[151]  J. Gołąb,et al.  Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2'-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[152]  Bin Yu,et al.  All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. , 2003, Cancer research.

[153]  R. Schreiber,et al.  Cancer immunoediting: from immunosurveillance to tumor escape , 2002, Nature Immunology.

[154]  R. Offringa,et al.  Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine , 2001, The Journal of experimental medicine.

[155]  I. Svane,et al.  Methylcholanthrene‐induced sarcomas in nude mice have short induction times and relatively low levels of surface MHC class I expression , 1996, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[156]  N. Van Rooijen,et al.  Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. , 1994, Journal of immunological methods.

[157]  M. van Glabbeke,et al.  The EORTC Early Clinical Trials Cooperative Group experience with 5-aza-2'-deoxycytidine (NSC 127716) in patients with colo-rectal, head and neck, renal carcinomas and malignant melanomas. , 1987, European journal of cancer & clinical oncology.

[158]  K. Kakimi,et al.  Advances in personalized cancer immunotherapy , 2016, Breast Cancer.

[159]  A. Salem,et al.  Biodegradable Microparticles Loaded with Doxorubicin and CpG ODN for In Situ Immunization Against Cancer , 2014, The AAPS Journal.

[160]  D. Deeb,et al.  ROS mediate proapoptotic and antisurvival activity of oleanane triterpenoid CDDO-Me in ovarian cancer cells. , 2013, Anticancer research.