title: The tumor microenvironment: a target for combination therapy of breast cancer.
abstract: Cancer immunotherapy is in the midst of a major paradigm shift from an approach primarily focused on attacking tumor cells to a strategy also targeting the tumor microenvironment (TME).  This strategy is designed for the use of combination therapies, several of which are reviewed here.  Particular emphasis is placed on targeting such components of the TME as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) overexpressing specific therapy targets such as Legumain, an asparaginyl endopeptidase, proto-oncogene  Fra-1, transcription factor Stat3 and fibroblast activation protein (FAP) as well as HER-2, respectively.  The use of DNA vaccines directed against some of these targets overexpressed on both breast tumor cells as well as TAMs and CAFs in the TME results in the elimination of tumor growth, progression, metastasis and recurrence in mouse tumor models.  This type of cancer therapy is significantly improved in efficacy by a strategy specifically designed to combine immunotherapies, including DNA vaccines, with a novel chemotherapy featuring highly effective nanoparticle-mediated drug delivery, specifically targeted to tumor cells as well as key components of the TME, leading to its modulation and subsequent elimination of tumor growth, metastasis, and, most importantly, suppression of tumor recurrence.
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. reisfeld@scripps.edu
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000008:administration & dosage; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage*; D000099240:Asparaginyl Endopeptidase
chemical_list: D003546:Cysteine Endopeptidases; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA; D000099240:Asparaginyl Endopeptidase; C000715470:MAS1 protein, human