During the past decade, great efforts have been dedicated to the development of clinically relevant interventions that would trigger potent (and hence potentially curative) anticancer immune responses. Indeed, developing neoplasms normally establish local and systemic immunosuppressive networks that inhibit tumor-targeting immune effector cells, be them natural or elicited by (immuno)therapy. One possible approach to boost anticancer immunity consists in the (generally systemic) administration of recombinant immunostimulatory cytokines. In a limited number of oncological indications, immunostimulatory cytokines mediate clinical activity as standalone immunotherapeutic interventions. Most often, however, immunostimulatory cytokines are employed as immunological adjuvants, i.e., to unleash the immunogenic potential of other immunotherapeutic agents, like tumor-targeting vaccines and checkpoint blockers. Here, we discuss recent preclinical and clinical advances in the use of some cytokines as immunostimulatory agents in oncological indications.

Group of Immune receptors of the Innate and Adaptive System Institut d'Investigacions Biomédiques August Pi i Sunyer

Gustave Roussy Cancer Campus Villejuif France

Gustave Roussy Cancer Campus Villejuif France; INSERM U1015 CICBT507 Villejuif France

INSERM U1138 Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer Center de Recherche des Cordeliers Paris France; Gustave Roussy Cancer Campus Villejuif France

INSERM U1138 Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer Center de Recherche des Cordeliers Paris France; Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France; Metabolomics and Cell Biology Platforms Gustave Roussy Cancer Campus Villejuif France; Department of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

INSERM U1138 Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Equipe 13 Center de Recherche des Cordeliers Paris France

INSERM U1138 Paris France; Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France; Université Pierre et Marie Curie Paris 6 Paris France; Laboratory of Integrative Cancer Immunology Center de Recherche des Cordeliers Paris France

Sotio Prague Czech Republic; Dept of Immunology 2nd Faculty of Medicine and University Hospital Motol Charles University Prague Czech Republic

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Wang J, Lin D, Peng H, Shao J, Gu J. Cancer-derived immunoglobulin G promotes LPS-induced proinflammatory cytokine production via binding to TLR4 in cervical cancer cells. Oncotarget 2014; 5:9727-43; PMID:25179302; http://dx.doi.org/10.18632/oncotarget.2359 PubMed DOI PMC

Huang SW, Kao JK, Wu CY, Wang ST, Lee HC, Liang SM, Chen YJ, Shieh JJ. Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells. Oncotarget 2014; 5:1363-81; PMID:24658058; http://dx.doi.org/10.18632/oncotarget.1734 PubMed DOI PMC

Vacchelli E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2013; 2:e25238; PMID:24083080; http://dx.doi.org/10.4161/onci.25238 PubMed DOI PMC

Aranda F, Vacchelli E, Obrist F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Henrik Ter Meulen J, Zitvogel L, Kroemer G et al. . Trial Watch: Toll-like receptor agonists in oncological indications. Oncoimmunology 2014; 3:e29179; PMID:25083332; http://dx.doi.org/10.4161/onci.29179 PubMed DOI PMC

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Kasai K, Kooka Y, Suzuki Y, Suzuki A, Oikawa T, Ushio A, Kasai Y, Sawara K, Miyamoto Y, Oikawa K et al. . Efficacy of hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced intrahepatic cholangiocarcinoma. Ann Surg Oncol 2014; 21:3638-45; PMID:24817369; http://dx.doi.org/10.1245/s10434-014-3766-7 PubMed DOI

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Baek S, Kim YM, Kim SB, Kim CS, Kwon SW, Kim Y, Kim H, Lee H. Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial. Cell Mol Immunol 2015; 12:87-95; PMID:24976269; http://dx.doi.org/10.1038/cmi.2014.40 PubMed DOI PMC

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Elkord E, Burt DJ, Sundstedt A, Nordle O, Hedlund G, Hawkins RE. Immunological response and overall survival in a subset of advanced renal cell carcinoma patients from a randomized phase 2/3 study of naptumomab estafenatox plus IFN-alpha versus IFN-alpha. Oncotarget 2015; 6:4428-39; PMID:25669986; http://dx.doi.org/10.18632/oncotarget.2922 PubMed DOI PMC

Jarvinen R, Marttila T, Kaasinen E, Rintala E, Aaltomaa S, Kallio J, Liukkonen T, Puolakka VM, Seppänen M, Tuhkanen K et al. . Long-term outcome of patients with frequently recurrent non-muscle-invasive bladder carcinoma treated with one perioperative plus four weekly instillations of mitomycin C followed by monthly bacillus calmette-guerin (BCG) or alternating BCG and interferon-alpha2b instillations: Prospective randomised finnBladder-4 study. Eur Urol 2015; 68:611-7; PMID:25748117; http://dx.doi.org/10.1016/j.eururo.2015.02.022 PubMed DOI

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Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J et al. . Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015; 16:795-803; PMID:26095785; http://dx.doi.org/10.1016/S1470-2045(15)00054-6 PubMed DOI

Song L, Zhou X, Li X. Phase II trial of granulocyte-macrophage colony-stimulating factor plus thalidomide in older patients with castration-resistant prostate cancer. Mol Clin Oncol 2015; 3:865-8; PMID:26171197; http://dx.doi.org/10.3892/mco.2015.571 PubMed DOI PMC

Dijkgraaf EM, Santegoets SJ, Reyners AK, Goedemans R, Wouters MC, Kenter GG, van Erkel AR, van Poelgeest MI, Nijman HW, van der Hoeven JJ et al. . A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha2b in patients with recurrent epithelial ovarian cancer. Ann Oncol 2015; 26:2141-9; PMID:26216383; http://dx.doi.org/10.1093/annonc/mdv309 PubMed DOI

Eto M, Kawano Y, Hirao Y, Mita K, Arai Y, Tsukamoto T, Hashine K, Matsubara A, Fujioka T, Kimura G et al. . Phase II clinical trial of sorafenib plus interferon-alpha treatment for patients with metastatic renal cell carcinoma in Japan. BMC Cancer 2015; 15:667; PMID:26452347; http://dx.doi.org/10.1186/s12885-015-1675-1 PubMed DOI PMC

Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM et al. . Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol 2015; 33:74-82; PMID:25403209; http://dx.doi.org/10.1200/JCO.2014.57.3329 PubMed DOI PMC

Galluzzi L. New immunotherapeutic paradigms for castration-resistant prostate cancer. Oncoimmunology 2013; 2:e26084; http://dx.doi.org/10.4161/onci.26084 PubMed DOI PMC

Semeraro M, Galluzzi L. Novel insights into the mechanism of action of lenalidomide. Oncoimmunology 2014; 3:e28386; PMID:25340011; http://dx.doi.org/10.4161/onci.28386 PubMed DOI PMC

Semeraro M, Vacchelli E, Eggermont A, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Lenalidomide-based immunochemotherapy. Oncoimmunology 2013; 2:e26494; PMID:24482747; http://dx.doi.org/10.4161/onci.26494 PubMed DOI PMC

Vacchelli E, Vitale I, Tartour E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Anticancer radioimmunotherapy. Oncoimmunology 2013; 2:e25595; PMID:24319634; http://dx.doi.org/10.4161/onci.25595 PubMed DOI PMC

Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 2014; 5:403-16; PMID:24480782; http://dx.doi.org/10.18632/oncotarget.1719 PubMed DOI PMC

Bloy N, Pol J, Manic G, Vitale I, Eggermont A, Galon J, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Radioimmunotherapy for oncological indications. Oncoimmunology 2014; 3:e954929; PMID:25941606; http://dx.doi.org/10.4161/21624011.2014.954929 PubMed DOI PMC

Mesange P, Poindessous V, Sabbah M, Escargueil AE, de Gramont A, Larsen AK. Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. Oncotarget 2014; 5:4709-21; PMID:25015210; http://dx.doi.org/10.18632/oncotarget.1671 PubMed DOI PMC

Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology 2014; 3:e27048; PMID:24605265; http://dx.doi.org/10.4161/onci.27048 PubMed DOI PMC

Chen P, Bonaldo P. Role of macrophage polarization in tumor angiogenesis and vessel normalization: implications for new anticancer therapies. Int Rev Cell Mol Biol 2013; 301:1-35; PMID:23317816; http://dx.doi.org/10.1016/B978-0-12-407704-1.00001-4 PubMed DOI

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Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 2013; 39:74-88; PMID:23890065; http://dx.doi.org/10.1016/j.immuni.2013.06.014 PubMed DOI

Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2014; 3:e27878; PMID:24800173; http://dx.doi.org/10.4161/onci.27878 PubMed DOI PMC

Vacchelli E, Senovilla L, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology 2013; 2:e23510; PMID:23687621; http://dx.doi.org/10.4161/onci.23510 PubMed DOI PMC

Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 2014; 32:752-9; PMID:24297945; http://dx.doi.org/10.1200/JCO.2013.50.5305 PubMed DOI

Cai Q, Chen Y, Zou D, Zhang L, Badillo M, Zhou S, Lopez E, Jiang W, Huang H, Lin T et al. . Clinical outcomes of a novel combination of lenalidomide and rituximab followed by stem cell transplantation for relapsed/refractory aggressive B-cell non-hodgkin lymphoma. Oncotarget 2014; 5:7368-80; PMID:25228589; http://dx.doi.org/10.18632/oncotarget.2255 PubMed DOI PMC

Wagner JY, Schwarz K, Schreiber S, Schmidt B, Wester HJ, Schwaiger M, Peschel C, von Schilling C, Scheidhauer K, Keller U. Myeloablative anti-CD20 radioimmunotherapy +/- high-dose chemotherapy followed by autologous stem cell support for relapsed/refractory B-cell lymphoma results in excellent long-term survival. Oncotarget 2013; 4:899-910; PMID:23765188; http://dx.doi.org/10.18632/oncotarget.1037 PubMed DOI PMC

Park MS, Kim BR, Dong SM, Lee SH, Kim DY, Rho SB. The antihypertension drug doxazosin inhibits tumor growth and angiogenesis by decreasing VEGFR-2/Akt/mTOR signaling and VEGF and HIF-1alpha expression. Oncotarget 2014; 5:4935-44; PMID:24952732; http://dx.doi.org/10.18632/oncotarget.2064 PubMed DOI PMC

Blagosklonny MV. Immunosuppressants in cancer prevention and therapy. Oncoimmunology 2013; 2:e26961; PMID:24575379; http://dx.doi.org/10.4161/onci.26961 PubMed DOI PMC

Pezzolo A, Marimpietri D, Raffaghello L, Cocco C, Pistorio A, Gambini C, Cilli M, Horenstein A, Malavasi F, Pistoia V. Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia. Oncotarget 2014; 5:10368-81; PMID:25362644; http://dx.doi.org/10.18632/oncotarget.2015 PubMed DOI PMC

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Duffy MJ, Crown J, Mullooly M. ADAM10 and ADAM17: New players in trastuzumab tesistance. Oncotarget 2014; 5:10963-4; PMID:25460503; http://dx.doi.org/10.18632/oncotarget.2794 PubMed DOI PMC

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Dinutuximab approved for high-risk neuroblastoma. Cancer Discov 2015; 5:OF5; PMID:25851859; http://dx.doi.org/2548405510.1158/2159-8290.CD-NB2015-044 PubMed DOI

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Ceresa BP, Peterson JL. Cell and molecular biology of epidermal growth factor receptor. Int Rev Cell Mol Biol 2014; 313:145-78; PMID:25376492; http://dx.doi.org/10.1016/B978-0-12-800177-6.00005-0 PubMed DOI

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Radiotherapy in Combination With Cytokine Treatment

Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

Trial watch: Immune checkpoint blockers for cancer therapy