Targeting both cancer cells and immune cells may be the key to fight metastasis.

Conventional anticancer therapies, such as chemotherapy, radiotherapy, and targeted therapy, are designed to kill cancer cells. However, the efficacy of anticancer therapies is not only determined by their direct effects on cancer cells but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit several changes in immune-related parameters including the composition, phenotype, and function of immune cells. Here we discuss the impact of innate and adaptive immune cells on the success of anticancer therapy. In this context we examine the opportunities to exploit host immune responses to boost tumor clearing, and highlight the challenges facing the treatment of advanced metastatic disease.

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Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy.

Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer.

Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer.

Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects.

Regulation of T cells by mTOR: the known knowns and the known unknowns.

Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40.

CD4 + T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation.

Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway.

Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy.

Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice.

Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells.

New paradigms and future challenges in radiation oncology: an update of biological targets and technology.

Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.

Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.

CD4 + CD25 + regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.

The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor.

Role of host defense merchanisms in the antitumor activity of adriamycin and daunomycin in mice.

Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders.

The blood and bone marrow in yellow cross gas (mustard gas) poisoning: changes produced in the bone marrow of fatal cases.

Glossary

a class of chemotherapy drugs that directly damage DNA by substituting alkyl groups for hydrogen atoms on DNA, causing the formation of crosslinks within DNA chains and thereby resulting in cell death. Examples of alkylating agents are cyclophosphamide and melphalan.

a class of chemotherapy drugs that are widely used to treat many different types of cancer. Anthracyclines prevent cell division by disrupting the structure of the DNA via several mechanisms. Examples of anthracyclines are doxorubicin and daunorubicin.

a conditional GEMM of melanoma driven by an activated form of BRAF and loss of PTEN under the control of the tyrosinase (Tyr) promoter. Tumors are induced by topical administration of tamoxifen to the skin, and therefore the timing of tumor development can be initiated as desired.

a GEMM model in which SV40 large T antigen (Tag) expression under the control of the 5′ flanking region of the C3(1) component of the rat prostate steroid-binding protein drives tumor development. In females, mammary ductal epithelium is transformed leading to invasive mammary tumors that resemble human ductal carcinoma in situ (DCIS). Male mice develop phenotypic changes in the prostate that progress into invasive carcinoma.

in GEMMs for cancer, normal cells are transformed in situ as a consequence of germline or somatic mutations in specific cell types, resulting in the development of spontaneous tumors that faithfully recapitulate each stage of cancer progression – from tumor initiation to advanced disease and in some models also metastasis.

a GEMM for de novo squamous carcinogenesis of the skin. These mice transgenically express the early region genes of the human papilloma-virus type 16 (HPV16) under control of the human keratin 14 promoter/enhancer. Cervical tumors can also be induced in these mice by administration of low-dose estrogen, hence K14-HPV16/E 2 .

a conditional GEMM for invasive lobular breast cancer. These mice transgenically express Cre recombinase under the control of the human keratin 14 promoter. In these mice, the alleles encoding E-cadherin and p53 are homozygously floxed. As a consequence, mammary and skin epithelial cells stochastically lose E-cadherin and p53, which induces the formation of tumors in these tissues.

these mice carry a gain-of-function point mutation on one allele of the Kit receptor gene predisposing them to spontaneous gastrointestinal stromal tumor (GIST) development.

cancer dissemination is a multistep process, consisting of the following steps: local invasion at the primary tumor site, intravasation and survival into the circulation, extravasation and survival at distant sites, adaptation to a foreign microenvironment, and outgrowth of a metastasis. During every step of the metastatic cascade, cancer cells encounter normal host cells, such as immune cells. Interactions between disseminated cancer cells and normal host cells largely dictate the success of metastasis formation.

a GEMM for HER2+ breast cancer in which wild type rat ERBB2 expression is driven by the mouse mammary tumor virus (MMTV) promoter, which is only active in the mammary gland. These mice develop multifocal tumors in all 10 mammary glands, as well as spontaneous lung metastases in most mice. They are maintained on the FVB/n background.

similar to MMTV-Neu mice, this GEMM represents another model for HER2+ breast cancer. However, a mutated form of the rat proto-oncogene, ERBB2, is expressed under control of the MMTV promoter in this case. Multifocal tumors also arise in these mice from all five pairs of mammary glands and they develop spontaneous lung metastases. These mice are usually maintained on the BALB/c background.

a GEMM for mammary tumorigenesis. These mice transgenically express the polyomavirus middle T antigen (PyMT) oncogene under the control of the MMTV promoter. These mice develop multifocal tumors in all 10 mammary glands, as well as spontaneous lung metastases.

fresh tumor tissue from patients undergoing surgery is implanted into immunodeficient mice (usually NOD/SCID/Il2rg, otherwise known as NSG, mice) directly or following enzymatic digestion. Tumors can be grafted subcutaneously or orthotopically. PDX tumors are serially passaged in additional mice.

a conditional GEMM for Pten-deficient prostate cancer, where loss of Pten expression is driven by the probasin promoter. These mice develop prostatic intraepithelial neoplasia (PIN) lesions that progress to invasive adenocarcinomas.

a class of platinum-containing chemotherapy drugs that bind to and crosslink DNA, resulting in apoptosis. Examples of platinum compounds are cisplatin, carboplatin, and oxaliplatin.

a conditional GEMM of pancreatic cancer, in which the rat insulin gene promoter drives sporadic expression of SV40 large T antigen (Tag) in a subset of pancreatic β cells. Unlike RIP-Tag2 mice that are systemically tolerant to SV40 large T antigen, these mice develop an autoimmune response against the oncogene-expressing beta cells.

a class of chemotherapy drugs that disrupt microtubule function, and thus inhibit mitosis. Taxanes were first derived from plants of the yew tree. Examples of taxanes are paclitaxel and docetaxel.

in addition to cancer cells, many ‘normal’ cells are recruited to and activated in tumors. The tumor microenvironment is composed of many different types of immune cells, fibroblasts (referred to as cancer-associated fibroblasts), endothelial cells and other cells that normally reside in the organ afflicted by the tumor (e.g., adipocytes in breast cancer), soluble mediators, and the extracellular matrix (ECM). Throughout cancer progression there is extensive crosstalk between normal cells, soluble mediators, and cancer cells. These interactions largely dictate tumor behavior and therapy response. Each tumor type and each tumor stage is characterized by a unique tumor microenvironment.