Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade
Hanna Grauers Wiktorin, Malin S Nilsson, Roberta Kiffin, Frida Ewald Sander, Brianna Lenox, Anna Rydström, Kristoffer Hellstrand, Anna Martner, Hanna Grauers Wiktorin, Malin S Nilsson, Roberta Kiffin, Frida Ewald Sander, Brianna Lenox, Anna Rydström, Kristoffer Hellstrand, Anna Martner
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.e. EL-4 lymphoma, MC-38 colorectal carcinoma, and 4T1 mammary carcinoma. In vivo treatment with HDC delayed EL-4 and 4T1 tumor growth and reduced the ROS formation by intratumoral MDSCs. HDC treatment of EL-4 bearing mice also reduced the accumulation of intratumoral MDSCs and reduced MDSC-induced suppression of T cells ex vivo. Experiments using GR1-depleted and Nox2 knock out mice supported that the anti-tumor efficacy of HDC required presence of NOX2+ GR1+ cells in vivo. In addition, treatment with HDC enhanced the anti-tumor efficacy of programmed cell death receptor 1 (PD-1) and PD-1 ligand checkpoint blockade in EL-4- and MC-38-bearing mice. Immunomodulatory effects of a HDC-containing regimen on MDSCs were further analyzed in a phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996) where patients with acute myeloid leukemia received HDC in conjunction with low-dose IL-2 (HDC/IL-2) for relapse prevention. Peripheral CD14+HLA-DR-/low MDSCs (M-MDSCs) were reduced during cycles of HDC/IL-2 therapy and a pronounced reduction of M-MDSCs during HDC/IL-2 treatment heralded favorable clinical outcome. We propose that anti-tumor properties of HDC may comprise the targeting of MDSCs.
Keywords: Checkpoint inhibition; Histamine dihydrochloride; Myeloid-derived suppressor cells; NOX2; PD-1; Reactive oxygen species.
Conflict of interest statement
Conflict of interestAuthors Hanna Grauers Wiktorin, Frida Ewald Sander, Anna Martner, and Kristoffer Hellstrand hold issued or pending patents protecting the use of histamine and/or α-PD-1/α-PD-L1 therapy in cancer treatment. Kristoffer Hellstrand was previously a consultant to the Re:Mission study sponsor (Meda Pharma). Authors Kristoffer Hellstrand and Anna Martner have received honoraria and/or travel grants from the study sponsor. The other authors declare no potential conflicts of interest.
Ethical approval and ethical standardsThe clinical phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996), was approved by the Regional ethical review board in Gothenburg on June 2, 2009, application number 267-09. All procedures of this study were performed in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All animal experiments were performed according to the institutional guidelines and approved by the Research Animal Ethics Committee in Gothenburg on April 4, 2014, application number 86-2014.
Informed consentInformed consent was obtained from all individual participants before enrollment to the phase IV AML Trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996).
Animal sourceC57BL/6J and BALB/c mice were purchased from the Charles River Laboratories (Sulzfeld, Germany). B6.129S6-Cybbtm1Din (Nox2- KO) mice were originally obtained from the Jackson Laboratory (Bar Harbor, ME, USA) and bred in-house.
Cell line authenticationThe EL-4 lymphoma cell line and the 4T1 mammary cancer cell line originated from the American Type Culture Collection (ATCC) and were provided by Ingo Schmitz (Otto von Guericke University, Germany) and Göran Landberg (University of Gothenburg, Sweden), respectively. The MC-38 colon carcinoma cell line originated from the Developmental Therapeutics Program Tumor Repository (Frederick National Laboratory, USA) and was provided by Sukanya Raghavan (University of Gothenburg, Sweden). All cell lines were expanded and frozen in aliquots and were cultured for no more than one week after thawing prior to use in in vivo experiments. Authentication by SNP or STR is not currently standardized for murine cell lines.
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References
- Ribechini E, Greifenberg V, Sandwick S, Lutz M. Subsets, expansion and activation of myeloid-derived suppressor cells. Med Microbiol Immunol. 2010;199(3):273–281. doi: 10.1007/s00430-010-0151-4.
- Karlsson A, Dahlgren C. Assembly and activation of the neutrophil NADPH oxidase in granule membranes. Antioxid Redox Signal. 2002;4(1):49–60. doi: 10.1089/152308602753625852.
- Mellqvist UH, Hansson M, Brune M, Dahlgren C, Hermodsson S, Hellstrand K. Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine. Blood. 2000;96(5):1961–1968.
- Corzo CA, Cotter MJ, Cheng PY, Cheng FD, Kusmartsev S, Sotomayor E, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol. 2009;182(9):5693–5701. doi: 10.4049/jimmunol.0900092.
- Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016
- Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Investig. 2015;125(9):3356–3364. doi: 10.1172/JCI80005.
- Kotsakis A, Harasymczuk M, Schilling B, Georgoulias V, Argiris A, Whiteside TL. Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. J Immunol Methods. 2012;381(1–2):14–22. doi: 10.1016/j.jim.2012.04.004.
- Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol. 2012;91(1):167–181. doi: 10.1189/jlb.0311177.
- Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181(8):5791–5802. doi: 10.4049/jimmunol.181.8.5791.
- Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–689. doi: 10.4049/jimmunol.166.1.678.
- Mao YM, Eissler N, Le Blanc K, Johnsen JI, Kogner P, Kiessling R. Targeting suppressive myeloid cells potentiates checkpoint inhibitors to control spontaneous neuroblastoma. Clin Cancer Res. 2016;22(15):3849–3859. doi: 10.1158/1078-0432.CCR-15-1912.
- Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, Katsanis E, Larmonier N. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014;74(1):104–118. doi: 10.1158/0008-5472.CAN-13-1545.
- Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010;16(6):1812–1823. doi: 10.1158/1078-0432.CCR-09-3272.
- Kusmartsev S, Cheng FD, Yu B, Nefedova Y, Sotomayor E, Lush R, Gabrilovich D. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 2003;63(15):4441–4449.
- Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185–1196. doi: 10.1093/ajcn/85.5.1185.
- Martner A, Wiktorin HG, Lenox B, Sander FE, Aydin E, Aurelius J, Thoren FB, Stahlberg A, Hermodsson S, Hellstrand K. Histamine promotes the development of monocyte-derived dendritic cells and reduces tumor growth by targeting the myeloid NADPH oxidase. J Immunol. 2015;194(10):5014–5021. doi: 10.4049/jimmunol.1402991.
- Yang XD, Ai W, Asfaha S, Bhagat G, Friedman RA, Jin GC, Park H, Shykind B, Diacovo TG, Falus A, Wang TC. Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b(+)Ly6G(+) immature myeloid cells. Nat Med. 2011;17(1):87–263. doi: 10.1038/nm.2278.
- Martner A, Thoren FB, Aurelius J, Hellstrand K. Immunotherapeutic strategies for relapse control in acute myeloid leukemia. Blood Rev. 2013;27(5):209–216. doi: 10.1016/j.blre.2013.06.006.
- Dahlgren C, Karlsson A. Respiratory burst in human neutrophils. J Immunol Methods. 1999;232(1–2):3–14. doi: 10.1016/S0022-1759(99)00146-5.
- Rydström A, Hallner A, Aurelius J, Sander FE, Bernson E, Kiffin R, Thoren FB, Hellstrand K, Martner A. Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia. J Leukoc Biol. 2017
- Sander FE, Nilsson M, Rydström A, Aurelius J, Riise RE, Movitz C, Bernson E, Kiffin R, Ståhlberg A, Brune M, Foà R, Hellstrand K, Thorén FB, Martner A. Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy. Cancer Immunol Immunother. 2017;66(11):1473–1484. doi: 10.1007/s00262-017-2040-9.
- Qin H, Lerman B, Sakamaki I, Wei GW, Cha SCC, Rao SS, Qian JF, Hailemichael Y, Nurieva R, Dwyer KC, Roth J, Yi Q, Overwijk WW, Kwak LW. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med. 2014;20(6):676–681. doi: 10.1038/nm.3560.
- Sagiv-Barfi I, Kohrt HEK, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA. 2015;112(9):E966–E972. doi: 10.1073/pnas.1500712112.
- Aydin E, Johansson J, Nazir FH, Hellstrand K, Martner A. Role of NOX2-derived reactive oxygen species in NK cell-mediated control of murine melanoma metastasis. Cancer Immunol Res. 2017;5(9):804–811. doi: 10.1158/2326-6066.CIR-16-0382.
- Kiffin R, Wiktorin HG, Nilsson MS, Aurelius J, Aydin E, Lenox B, Nilsson JA, Ståhlberg A, Thorén FB, Hellstrand K, Martner A. Anti-leukemic properties of histamine in monocytic leukemia: the role of NOX2. Front Oncol. 2018
- Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 2007;67(22):11021–11028. doi: 10.1158/0008-5472.CAN-07-2593.
- Sun H, Li Y, Zhang ZF, Ju Y, Li L, Zhang BC, Liu B. Increase in myeloid-derived suppressor cells (MDSCs) associated with minimal residual disease (MRD) detection in adult acute myeloid leukemia. Int J Hematol. 2015;102(5):579–586. doi: 10.1007/s12185-015-1865-2.
- Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006;66(18):9299–9307. doi: 10.1158/0008-5472.CAN-06-1690.
- Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HEK, Horn L, Lawrence DP, Rost S, Leabman M, Xiao YY, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–563+. doi: 10.1038/nature14011.
- Dirkx AEM, Egbrink M, Castermans K, van der Schaft DWJ, Thijssen V, Dings RPM, Kwee L, Mayo KH, Wagstaff J, Steege J, Griffioen AW. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte–endothelium interactions and infiltration in tumors. FASEB J. 2006;20(6):621–630. doi: 10.1096/fj.05-4493com.
- Hong M, Puaux AL, Huang C, Loumagne L, Tow C, Mackay C, Kato M, Prevost-Blondel A, Avril MF, Nardin A, Abastado JP. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 2011;71(22):6997–7009. doi: 10.1158/0008-5472.CAN-11-1466.
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