JPT-107700; No of Pages 57 Pharmacology & Therapeutics xxx (2020) xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Targeting the tumor immune microenvironment with “nutraceuticals”: From bench to clinical trials Laura Masuelli a,1, Monica Benvenuto b,c,1, Chiara Focaccetti c,d, Sara Ciuffa c, Sara Fazi a, Arianna Bei e, Martino Tony Miele f, Lucia Piredda g, Vittorio Manzari c, Andrea Modesti c, Roberto Bei c,h,⁎ a Department of Experimental Medicine, University of Rome “Sapienza”, Viale Regina Elena 324, 00161 Rome, Italy b Saint Camillus International University of Health and Medical Sciences, via di Sant’Alessandro 8, 00131 Rome, Italy c Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy d Department of Human Science and Promotion of the Quality of Life, San Raffaele University Rome, Via di Val Cannuta 247, 00166 Rome, Italy e Medical School, University of Rome “Tor Vergata”, 00133 Rome, Italy f Department of Experimental Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy g Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Rome, Italy h CIMER, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy article info abstract Available online xxxx The occurrence of immune effector cells in the tissue microenvironment during neoplastic progression is critical in determining tumor growth outcomes. On the other hand, tumors may also avoid immune system-mediated elimination by recruiting immunosuppressive leukocytes and soluble factors, which coordinate a tumor microen- Keywords: vironment that counteracts the efficiency of the antitumor immune response. Checkpoint inhibitor therapy re- Nutraceutical sults have indicated a way forward via activation of the immune system against cancer. Widespread evidence Tumor has shown that different compounds in foods, when administered as purified substances, can act as immuno- Tumor microenvironment modulators in humans and animals. Although there is no universally accepted definition of nutraceuticals, the Immune system term identifies a wide category of natural compounds that may impact health and disease statuses and includes purified substances from natural sources, plant extracts, dietary supplements, vitamins, phytonutrients, and var- ious products with combinations of functional ingredients. In this review, we summarize the current knowledge on the immunomodulatory effects of nutraceuticals with a special focus on the cancer microenvironment, highlighting the conceptual benefits or drawbacks and subtle cell- specific effects of nutraceuticals for envisioning future therapies employing nutraceuticals as chemoadjuvants. © 2020 Elsevier Inc. All rights reserved. Abbreviations: 4-MU, Coumarin 4-methylumbelliferone; APCs, Antigen presenting cells; ARG1, Arginase 1; ATRA, All-trans retinoic acid; BG, β-1,3/1,6-glucans derived from Saccharomyces cerevisiae; BMDCs, Bone marrow dendritic cells; CAFs, Cancer associated fibroblasts; CAPE, Caffeic acid phenethyl ester; ConA, Concanavalin A; COX, Cyclooxygenase; CR3, Complement receptor 3; CRC, Colorectal cancer; CTL, Cytotoxic T lymphocytes; CTLA4, Cytotoxic T-lymphocyte antigen-4; CUR, Curcumin; DATS, Diallyl trisulfide; DCs, Dendritic cells; DHA, Docosahexaenoic acid; DIM, 3,30-diindolylmethane; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; DOX, Doxorubicin; DSS, Dextran sulphate sodium; EAT, Ehrlich ascites tumor; ECM, Extracellular matrix; EGCG, Epigallocatechin-3-O-gallate; EGF, Epidermal growth factor; EMT, Epithelial-to-mesenchymal-transition; EPA, Eicosapentaenoic acid; FA, Fatty acids; GA, Gallic acid; GIST, Gastrointestinal stromal tumor; GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; GpS, Gynostemma pentaphyllum; GTE, Green tea extract; HA, Hyaluronan; HIF-1α, Hypoxia-inducible factor 1-alpha; HUVECs, Human umbilical vein endothelial cells; I3C, Indole-3-carbinol; ICAM-1, Intercellular adhesion molecule 1; IDO, Indoleamine 2,3-dioxygenase; IFN, Interferon; IgA, Immunoglobulin A; IL, Interleukin; ITCs, Isothiocyanates; LPS, Lipopolysaccharide; M1 or M2, Polarized macrophages; Man-3DG, α-mangostin 3-O-β-D-2-deoxyglucopyranoside; Man-6DG, α-mangostin 6-O-β-D-2-deoxyglucopyranoside; MCP-1, Monocyte chemoattractant protein-1; MDSCs, Myeloid-derived sup- pressor cells; MMPs, Matrix metalloproteinases; MVD, Microvessel density; NK, Natural killer; NO, Nitric oxide; Nrf2, Nuclear factor erythroid 2; NSCLC, Non-small cell lung cancer; P2Et, Gallotannin-rich standardized fraction; PBMC, Peripheral blood mononuclear cell; PIC, Piceatannol; PD-(L)1, Programmed death-1 and ligand; PFA, Poly-ferulic acid; PGE2, Prostaglandin E2; PMA, Phytoemoagglutinin; PMN, Polymorphonuclear; PPP, Picropodophyllin; PPP-40, Pinus koraiensis; PUFAs, Polyunsaturated fatty acids; RA, Retinoic acid; RES, Resveratrol; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; SCFA, Short-chain fatty acids; SDG, Secoisolariciresinol diglucoside; SFN, Sulforaphane; SOD, superoxide dismutases; STING, Stimulator of IFN genes; TAMs, Tumor-associated macrophages; tBregs, Tumor-evoked regulatory B cells; TGF-β, Transforming Growth Factor-β; TILs, Tumor infiltrating lymphocytes; TIMP, Tissue inhibitor of MMPs; TLRs, Toll-like receptor; TNF-α, Tumor necrosis factor-α;TPA,12-O-tetradecanoylphorbol-13-acetate; Tregs, Regulatory T cells; VEGF, Vascular endothelial growth factor; α-TEA, α-tocopheryloxyacetic acid; α-TOS, α-tocopheryl succinate. ⁎ Corresponding author at: Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy. E-mail address: [email protected] (R. Bei). 1Authors contributed equally to this work. https://doi.org/10.1016/j.pharmthera.2020.107700 0163-7258/© 2020 Elsevier Inc. All rights reserved. Please cite this article as: L. Masuelli, M. Benvenuto, C. Focaccetti, et al., Targeting the tumor immune microenvironment with “nutraceuticals”: From bench to clinical trials, Pharmacology & Therapeutics, https://doi.org/10.1016/j.pharmthera.2020.107700 L. Masuelli, M. Benvenuto, C. Focaccetti et al. Pharmacology & Therapeutics xxx (2020) xxx Contents 1. Introduction............................................... 0 2. Tumorimmunemicroenvironment..................................... 0 3. Nutraceutical and immune cell modulation in human and animal models in vitro and in vivo ........... 0 4. Modulationoftheimmuneresponsebynutraceuticalsemployedinclinicaltrials................ 0 5. SummaryandConclusion......................................... 0 DeclarationofCompetingofInterest....................................... 0 Acknowledgements.............................................. 0 References................................................... 0 1. Introduction microorganisms and nutraceutical enzymes and (b) nontraditional nutraceuticals including fortified and recombinant nutraceuticals The term "nutraceutical" was created by Dr. DeFelice from "nutri- (Chanda, Tiwari, Kumar, & Singh, 2019); or biochemical structure (Das tion" and "pharmaceutical" in 1989 (DeFelice, 2002; Kalra, 2003). To et al., 2012). Biochemical nutraceutical categories include phenols, date, there is no international consensus on the definition of “nutraceu- lipids, organic acids and polysaccharides, organosulfurs, phytic acid, tical” (Aronson, 2017). The Foundation for Innovation in Medicine phytosterols, and terpenes (Nwanodi, 2017)(Table 1). (FIM), of which Dr. DeFelice is the founder and chairman, defines “nutraceuticals” as a comprehensive term that includes foods, dietary supplements [as defined in the Dietary Supplement Health and Educa- 2. Tumor immune microenvironment tion Act (DSHEA)] and medical foods that have a health-medical benefit, including the prevention and/or treatment of disease (DeFelice, 2002). The occurrence of immune effector cells in the tissue microenviron- On the other hand, widespread evidence has shown that different com- ment during neoplastic progression is critical in determining the out- pounds in foods, when administered as purified substances, can act as come of tumor growth. The development of cancer cells induces an immunomodulators in humans and animals. An immunomodulator is immune response driven by cells of the innate immune system (innate a substance or agent that modifies immune responses through its im- lymphoid cells, natural killer (NK) T cells, γδ T cells, NK cells and macro- + + munomodulatory properties by regulating immune cells and their re- phages) and then by cytotoxic (CTL, CD8 ) and helper (TH,CD4 )T leased products (Spelman et al., 2006). lymphocytes producing interferon-γ (IFN-γ) that are recruited into In this review, we summarize the current knowledge on the im- the tumor microenvironment and induce cell death, further activation munomodulatory effects of nutraceuticals with a special focus of NK cells and macrophages, the humoral response and inflammation. on the cancer microenvironment, highlighting the conceptual ben- CTLs can kill target cancer cells by granzyme exocytosis and Fas ligand efits or drawbacks and subtle cell-specific effects of nutraceuticals (FasL)-mediated apoptosis induction and can secrete IFN-γ and tumor for envisioning future therapies employing nutraceuticals as necrosis factor-α (TNF-α) to induce cytotoxicity in cancer cells (Lei chemoadjuvants. et al., 2020). TH cells are essential for CTL function and action.