Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines

Butt, Afifaa; Mills, Kingston H. G.

doi:10.1038/onc.2013.432

Cited by 119 publications

(89 citation statements)

References 139 publications

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“…Several other Treg-targeting strategies are currently in development, including the use of daclizumab - a CD25 - neutralizing antibody and the blockade of CCL22. These strategies recently showed promise in preclinical models and in breast cancer clinical trials (60–62) but have not yet been tested in LM models. Clinical trials with combination checkpoint inhibitors Tremelimumab (anti-CTLA-4) and MEDI4736 (anti-PD-L1) have recently been initiated for patients with resectable CRCLM, aimed at reactivating immune surveillance in the TME (NCT02754856, phase 1, recruiting).…”

Section: B Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

Milette

Sicklick

Lowy

et al. 2017

Clinical Cancer Research

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Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal (GI) tract, with colorectal cancer (CRC) being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and non-parenchymal cells, that collectively create both pre-and pro-metastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: 1) the current therapeutic options for treating LM with a particular focus on CRC LM (CRCLM); 2) the role of the LME in LM at each of its phases 3) potential targets in the LME identified through pre-clinical and clinical investigations and 4) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM, as the basis for future clinical trials.

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Section: B Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

Milette

Sicklick

Lowy

et al. 2017

Clinical Cancer Research

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“…5,7 TAMs are recruited by various cytokines and chemokines, suppress the activity of cytotoxic T-lymphocytes via programmed cell death 1 ligand 1 (PD-L1) or B7-H4 and other receptors/mediators. 7,8 The mechanisms by which macrophages acquire prometastatic abilities have not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

et al. 2015

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Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 C , CD163 weak and CD68 C macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

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“…Recently, immune checkpoint receptors involved in regulating the immune reaction have been found to play a critical role in the antitumor immune response (Butt and Mills 2014). Thus, as a result of various clinical trials targeting immune checkpoints, various immune regulating genes are currently being considered as targets for drug development, as well as predictive or prognostic biomarkers in the treatment of metastatic CRC.…”

Section: Introductionmentioning

confidence: 99%