Intratumoral Injection of CpG Oligonucleotides Induces the Differentiation and Reduces the Immunosuppressive Activity of Myeloid-derived Suppressor Cells

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2012 Jan 11

PMID 22231700

Citations 138

Authors

Yuko Shirota

Hidekazu Shirota

Dennis M Klinman

Affiliations

Soon will be listed here.

Abstract

Immunostimulatory CpG oligonucleotides (ODN) activate cells that express TLR9 and have been shown to improve the host's response to tumor Ags. Unfortunately, the immunosuppressive microenvironment that surrounds many cancers inhibits Ag-specific cellular responses and thus interferes with CpG-mediated immunotherapy. Myeloid-derived suppressor cells (MDSC) represent an important constituent of this immunosuppressive milieu. Large numbers of MDSC are present in and near tumor sites where they inhibit the activity of Ag-specific T and NK cells. Current studies indicate that the delivery of CpG ODN directly into the tumor bed reduces the immunosuppressive activity of monocytic (CD11b(+), Ly6G(-), Ly6C(high)) MDSC. Monocytic MDSC express TLR9 and respond to CpG stimulation by 1) losing their ability to suppress T cell function, 2) producing Th1 cytokines, and 3) differentiating into macrophages with tumoricidal capability. These findings provide insight into a novel mechanism by which CpG ODN contribute to tumor regression, and they support intratumoral injection as the optimal route for their delivery.

Citing Articles

Harnessing myeloid cells in cancer.

Park S, Pylaeva E, Bhuria V, Gambardella A, Schiavoni G, Mougiakakos D Mol Cancer. 2025; 24(1):69.

PMID: 40050933 PMC: 11887392. DOI: 10.1186/s12943-025-02249-2.

Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy.

He S, Zheng L, Qi C Mol Cancer. 2025; 24(1):5.

PMID: 39780248 PMC: 11707952. DOI: 10.1186/s12943-024-02208-3.

An Open-Label Study of Subcutaneous CpG Oligodeoxynucleotide (PF03512676) in Combination with Trastuzumab in Patients with Metastatic HER2+ Breast Cancer.

Quiroga D, Wesolowski R, Zelinskas S, Pinette A, Benner B, Schwarz E Cancer Control. 2024; 31:10732748241250189.

PMID: 38797949 PMC: 11129578. DOI: 10.1177/10732748241250189.

Targeting the innate immune system in pediatric and adult AML.

Perzolli A, Koedijk J, Zwaan C, Heidenreich O Leukemia. 2024; 38(6):1191-1201.

PMID: 38459166 PMC: 11147779. DOI: 10.1038/s41375-024-02217-7.

Antitumoral effect of local injection of TLR-9 agonist emulsified in Lipiodol with systemic anti-PD-1 in a murine model of colorectal carcinoma.

Grindel A, Fretellier N, Soares M, Bouzakher N, Millot Maysounabe V, Santus R Front Immunol. 2024; 14:1272246.

PMID: 38292484 PMC: 10825566. DOI: 10.3389/fimmu.2023.1272246.

References

Murad Y, Clay T, Lyerly H, Morse M . CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy. Expert Opin Biol Ther. 2007; 7(8):1257-66. DOI: 10.1517/14712598.7.8.1257. View

Yin B, Ma G, Yen C, Zhou Z, Wang G, Divino C . Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. J Immunol. 2010; 185(10):5828-34. PMC: 4355963. DOI: 10.4049/jimmunol.0903636. View

Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W . Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006; 203(12):2691-702. PMC: 2118163. DOI: 10.1084/jem.20061104. View

Bronte V, Zanovello P . Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 2005; 5(8):641-54. DOI: 10.1038/nri1668. View

Klinman D . Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. 2004; 4(4):249-58. DOI: 10.1038/nri1329. View

Kawarada Y, Ganss R, Garbi N, Sacher T, Arnold B, Hammerling G . NK- and CD8(+) T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides. J Immunol. 2001; 167(9):5247-53. DOI: 10.4049/jimmunol.167.9.5247. View

Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C . Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2009; 40(1):22-35. DOI: 10.1002/eji.200939903. View

Zoglmeier C, Bauer H, Noerenberg D, Wedekind G, Bittner P, Sandholzer N . CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res. 2011; 17(7):1765-75. DOI: 10.1158/1078-0432.CCR-10-2672. View

Ostrand-Rosenberg S, Sinha P . Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009; 182(8):4499-506. PMC: 2810498. DOI: 10.4049/jimmunol.0802740. View

10.

Murad Y, Clay T . CpG oligodeoxynucleotides as TLR9 agonists: therapeutic applications in cancer. BioDrugs. 2009; 23(6):361-75. DOI: 10.2165/11316930-000000000-00000. View

11.

Baines J, Celis E . Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res. 2003; 9(7):2693-700. View

12.

Vicari A, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F . Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med. 2002; 196(4):541-9. PMC: 2196048. DOI: 10.1084/jem.20020732. View

13.

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

14.

Shirota H, Petrenko L, Hong C, Klinman D . Potential of transfected muscle cells to contribute to DNA vaccine immunogenicity. J Immunol. 2007; 179(1):329-36. DOI: 10.4049/jimmunol.179.1.329. View

15.

Lou Y, Liu C, Lizee G, Peng W, Xu C, Ye Y . Antitumor activity mediated by CpG: the route of administration is critical. J Immunother. 2011; 34(3):279-88. PMC: 6119202. DOI: 10.1097/CJI.0b013e31820d2a05. View

16.

Rodriguez P, Ochoa A . Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008; 222:180-91. PMC: 3546504. DOI: 10.1111/j.1600-065X.2008.00608.x. View

17.

Gabrilovich D, Nagaraj S . Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9(3):162-74. PMC: 2828349. DOI: 10.1038/nri2506. View

18.

Le H, Graham L, Cha E, Morales J, Manjili M, Bear H . 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; 9(7-8):900-9. DOI: 10.1016/j.intimp.2009.03.015. View

19.

Klimp A, de Vries E, Scherphof G, Daemen T . A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol Hematol. 2002; 44(2):143-61. DOI: 10.1016/s1040-8428(01)00203-7. View

20.

Hofmann M, Kors C, Audring H, Walden P, Sterry W, Trefzer U . Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma. J Immunother. 2008; 31(5):520-7. DOI: 10.1097/CJI.0b013e318174a4df. View