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BMC Immunology
Published in: BMC Immunology 1/2020

Open Access 01-12-2020 | Breast Cancer | Research article

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer

Authors: Andrea J. Luker, Laura J. Graham, Timothy M. Smith Jr, Carmen Camarena, Matt P. Zellner, Jamie-Jean S. Gilmer, Sheela R. Damle, Daniel H. Conrad, Harry D. Bear, Rebecca K. Martin

Published in: BMC Immunology | Issue 1/2020

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Abstract

Background

Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma.

Results

In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine’s versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model.

Conclusions

Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.
Appendix
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Literature
1.
Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001 Apr;134(7):573–86.PubMedCrossRef
2.
Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009 Jan;58(1):49–59.CrossRefPubMed
3.
Gonda K, Shibata M, Ohtake T, Matsumoto Y, Tachibana K, Abe N, et al. Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer. Oncol Lett. 2017;14(2):1766–74.PubMedPubMedCentralCrossRef
4.
Wang L, Chang EWY, Wong SC, Ong S-M, Chong DQY, Ling KL. Increased myeloid-derived suppressor cells in gastric Cancer correlate with Cancer stage and plasma S100A8/A9 Proinflammatory proteins. J Immunol. 2013;190(2):794–804.PubMedCrossRef
5.
Sio A, Chehal MK, Tsai K, Fan X, Roberts ME, Nelson BH, et al. Dysregulated hematopoiesiscausedbymammary Cancer is associated with epigenetic changes and Hox gene expression in hematopoietic cells. Cancer Res. 2013;73(19):5892–904.PubMedCrossRef
6.
Choi HS, Ha SY, Kim H-M, Ahn SM, Kang M-S, Kim K-M, et al. The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients. Oncotarget. 2016 Feb;7(7):7940–51.PubMedPubMedCentralCrossRef
7.
Ugel S, Peranzoni E, Desantis G, Chioda M, Walter S, Weinschenk T, et al. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep. 2012 Sep 27;2(3):628–39.PubMedCrossRef
8.
Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014 Jan;74(1):104–18.PubMedCrossRef
9.
Ostrand-Rosenberg S, Fenselau C. Myeloid-derived suppressor cells: immune-suppressive cells that impair antitumor immunity and are sculpted by their environment. J Immunol. 2018;200:422–31.PubMedCrossRef
10.
Terracina KP, Graham LJ, Payne KK, Manjili MH, Baek A, Damle SR, et al. DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer. Cancer Immunol Immunother. 2016 Sep;65(9):1061–73.PubMedPubMedCentralCrossRef
11.
Umansky V, Adema GJ, Baran J, Brandau S, Van Ginderachter JA, Hu X, et al. Interactions among myeloid regulatory cells in cancer. Cancer Immunol Immunother. Springer Science and Business Media Deutschland GmbH; 2019 Apr 2;68(4):645–60.
12.
Kapanadze T, Gamrekelashvili J, Ma C, Chan C, Zhao F, Hewitt S, et al. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J Hepatol. 2013 Nov;59(5):1007–13.PubMedPubMedCentralCrossRef
13.
Kim IS, Gao Y, Welte T, Wang H, Liu J, Janghorban M, et al. Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms. Nat Cell Biol Nature Publishing Group. 2019;21(9):1113–26.CrossRef
14.
Okła K, Czerwonka A, Wawruszak A, Bobiński M, Bilska M, Tarkowski R, et al. Clinical relevance and immunosuppressive pattern of circulating and infiltrating subsets of myeloid-derived suppressor cells (MDSCs) in epithelial ovarian cancer. Front Immunol. Frontiers Media S.A.; 2019;10(APR).
15.
Talmadge JE, Gabrilovich DI, Immunology TT. History of myeloid derived suppressor cells (MDSCs) in the macro- and micro-environment of tumour-bearing hosts. Nat Rev Cancer. 2013;13(10):739–52.PubMedPubMedCentralCrossRef
16.
duPre’ SA, Hunter KW. Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. Exp Mol Pathol 2007 Feb;82(1):12–24.PubMedCrossRef
17.
Bronte V, Wang M, Overwijk WW, Surman DR, Pericle F, Rosenberg SA, et al. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of mac-1+/gr-1+ cells. J Immunol NIH Public Access. 1998;161(10):5313–20.
18.
Kusmartsev SA, Li Y, Chen SH. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol. 2000;165(2):779–85.PubMedCrossRef
19.
Gibb DR, Saleem SJ, Kang D-J, Subler MA, Conrad DH. ADAM10 overexpression shifts lympho- and myelopoiesis by dysregulating site 2/site 3 cleavage products of notch. J Immunol. 2011;186(7):4244–52.PubMedCrossRef
20.
Saleem SJ, Martin RK, Morales JK, Sturgill JL, Gibb DR, Graham L, et al. Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity. J Immunol. 2012;189(2):511–5.PubMedCrossRef
21.
Martin RK, Saleem SJ, Folgosa L, Zellner HB, Damle SR, Nguyen G-KT, et al. Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells. J Leukoc Biol. 2014;
22.
Martin RK, Damle SR, Valentine YA, Zellner MP, James BN, Lownik JC, Luker AJ, Davis EH, DeMeules MM, Khandjian LM, Finkelman FD, Jr U, Joseph F, Conrad DH. B1 cell IgE impedes mast cell-mediated enhancement of parasite expulsion through B2 IgE blockade. Cell Rep. 2018;22(7):1824–34.PubMedPubMedCentralCrossRef
23.
Raber PL, Thevenot P, Sierra R, Wyczechowska D, Halle D, Ramirez ME, et al. Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways. Int J Cancer. 2014;134(12):2853–64.PubMedCrossRef
24.
Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in Cancer. Cancer Immunol Immunother. 2006 Mar;55(3):237–45.PubMedCrossRef
25.
Bronte V, Apolloni E, Cabrelle A, Ronca R, Serafini P, Zamboni P, et al. Identification of a CD11b(+)/gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood. 2000 Dec 1;96(12):3838–46.PubMedCrossRef
26.
Kusmartsev S, Gabrilovich DI. Inhibition of myeloid cell differentiation in cancer : the role of reactive oxygen species. Cancer. 2003;74(August).PubMedCrossRef
27.
Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM. Mechanism of immune dysfunction in cancer mediated by immature gr-1+ myeloid cells. J Immunol. 2001 May;166(9):5398–406.PubMedCrossRef
28.
Zhou J, Yao Y, Shen Q, Li G, Hu L, Zhang X. Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells. J Cancer Res Clin Oncol. 2017 Aug;143(8):1371–80.PubMedCrossRef
29.
Liu Y, Van Ginderachter JA, Brys L, De Baetselier P, Raes G, Geldhof AB. Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells. J Immunol. 2003;170(10):5064–74.PubMedCrossRef
30.
Chandrasekaran S, King M. Microenvironment of tumor-draining lymph nodes: opportunities for liposome-based targeted therapy. Int J Mol Sci. 2014 Nov;15(11):20209–39.PubMedPubMedCentralCrossRef
31.
Duan F, Simeone S, Wu R, Grady J, Mandoiu I, Srivastava PK. Area under the curve as a tool to measure kinetics of tumor growth in experimental animals. J Immunol Methods. 2012 Aug;382(1–2):224–8.PubMedCrossRef
32.
Triozzi PL, Aldrich W, Achberger S, Ponnazhagan S, Alcazar O, Saunthararajah Y. Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice. Cancer Immunol Immunother. 2012 Sep;61(9):1441–50.PubMedCrossRef
33.
Lucarini V, Buccione C, Ziccheddu G, Peschiaroli F, Sestili P, Puglisi R, et al. Combining type I Interferons and 5-Aza-2′-Deoxycitidine to improve anti-tumor response against melanoma. J Invest Dermatol. 2017;137(1):159–69.PubMedCrossRef
34.
Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol. 2009 Jul;9(7–8):900–9.PubMedCrossRef
35.
Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005 Sep;11(18):6713–21.PubMedCrossRef
36.
Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel Chemoimmunomodulating property of Docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010 Sep;16(18):4583–94.PubMedCrossRef
37.
Liu Y, Wei G, Cheng WA, Dong Z, Sun H, Lee VY, et al. Targeting myeloid-derived suppressor cells for cancer immunotherapy. Cancer Immunol Immunother. 2018 Aug;67(8):1181–95.PubMedCrossRef
38.
Lang S, Bruderek K, Kaspar C, Höing B, Kanaan O, Dominas N, et al. Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin Cancer Res. American Association for Cancer Research Inc.; 2018 Oct 1;24(19):4834–44.
39.
Bonavita E, Galdiero MR, Jaillon S, Mantovani A. Phagocytes as corrupted policemen in Cancer-related inflammation. Adv Cancer Res. 2015;128:141–71.PubMedCrossRef
40.
Long AH, Highfill SL, Cui Y, Smith JP, Walker AJ, Ramakrishna S, et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res. American Association for Cancer Research Inc.; 2016 Oct 1;4(10):869–80.
41.
Albeituni SH, Ding C, Liu M, Hu X, Luo F, Kloecker G, et al. Yeast-derived particulate β-Glucan treatment subverts the suppression of myeloid-derived suppressor cells (MDSC) by inducing Polymorphonuclear MDSC apoptosis and Monocytic MDSC differentiation to APC in Cancer. J Immunol. 2016 Mar 1;196(5):2167–80.PubMedCrossRef
42.
Vila-Leahey A, Oldford SA, Marignani PA, Wang J, Haidl ID, Marshall JS. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice. Oncoimmunology. 2016;5(7):e1151591.PubMedPubMedCentralCrossRef
43.
Unkeless JC. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte fc receptors. J Exp Med Rockefeller University Press. 1979;150(3):580–96.
44.
Challen GA, Boles N, Lin KKY, Goodell MA. Mouse hematopoietic stem cell identification and analysis. Vol. 75, Cytometry Part A. 2009. p. 14–24.CrossRef
45.
Chaimowitz NS, Martin RK, Cichy J, Gibb DR, Patil P, Kang D-J, et al. A disintegrin and metalloproteinase 10 regulates antibody production and maintenance of lymphoid architecture. J Immunol. 2011;187(10):5114–22.PubMedCrossRef
Metadata
Title
The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth in combination with adoptive immunotherapy in a mouse model of breast cancer
Authors
Andrea J. Luker
Laura J. Graham
Timothy M. Smith Jr
Carmen Camarena
Matt P. Zellner
Jamie-Jean S. Gilmer
Sheela R. Damle
Daniel H. Conrad
Harry D. Bear
Rebecca K. Martin
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2020
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-020-0337-5

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