Development of macrophage-targeted therapy using peptide/protein-loaded extracellular vesicles

[1]

P. Krzyszczyk, R. Schloss, A. Palmer, F. Berthiaume, The role of macrophages in acute

and chronic wound healing and interventions to promote pro-wound healing phenotypes,

Front. Physiol. 9 (2018) 1–22. https://doi.org/10.3389/fphys.2018.00419.

[2]

E. Woith, G. Fuhrmann, M.F. Melzig, Molecular Sciences Extracellular VesiclesConnecting Kingdoms, Int. J. Mol. Sci. 20 (2019) 5695.

[3]

M. Tkach, C. Théry, Communication by Extracellular Vesicles: Where We Are and

Where We Need to Go, Cell. 164 (2016) 1226–1232.

https://doi.org/10.1016/j.cell.2016.01.043.

[4]

J. Kowal, M. Tkach, C. Théry, Biogenesis and secretion of exosomes, Curr. Opin. Cell

Biol. 29 (2014) 116–125. https://doi.org/10.1016/j.ceb.2014.05.004.

[5]

G. Van Niel, G. D’Angelo, G. Raposo, Shedding light on the cell biology of extracellular

vesicles, Nat. Rev. Mol. Cell Biol. 19 (2018) 213–228.

https://doi.org/10.1038/nrm.2017.125.

[6]

T. Imai, Y. Takahashi, M. Nishikawa, K. Kato, M. Morishita, T. Yamashita, A.

Matsumoto, C. Charoenviriyakul, Y. Takakura, Macrophage-dependent clearance of

systemically administered B16BL6-derived exosomes from the blood circulation in

mice, J. Extracell. Vesicles. 4 (2015) 1–8. https://doi.org/10.3402/jev.v4.26238.

[7]

A. Matsumoto, Y. Takahashi, M. Nishikawa, K. Sano, M. Morishita, C.

Charoenviriyakul, H. Saji, Y. Takakura, Role of Phosphatidylserine-Derived Negative

Surface Charges in the Recognition and Uptake of Intravenously Injected B16BL6Derived Exosomes by Macrophages, J. Pharm. Sci. 106 (2017) 168–175.

https://doi.org/10.1016/j.xphs.2016.07.022.

[8]

D.B. Nguyen, T.B. Thuy Ly, M.C. Wesseling, M. Hittinger, A. Torge, A. Devitt, Y.

Perrie, I. Bernhardt, Characterization of microvesicles released from human red blood

cells, Cell. Physiol. Biochem. 38 (2016) 1085–1099. https://doi.org/10.1159/000443059.

[9]

M. Xu, Q. Yang, X. Sun, Y. Wang, Recent Advancements in the Loading and

Modification of Therapeutic Exosomes, Front. Bioeng. Biotechnol. 8 (2020).

https://doi.org/10.3389/fbioe.2020.586130.

[10]

A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati, The chemokine

system in diverse forms of macrophage activation and polarization, Trends Immunol. 25

(2004) 677–686. https://doi.org/10.1016/j.it.2004.09.015.

47

[11]

J.F. Rossi, Z.Y. Lu, M. Jourdan, B. Klein, Interleukin-6 as a therapeutic target, Clin.

Cancer Res. 21 (2015) 1248–1257. https://doi.org/10.1158/1078-0432.CCR-14-2291.

[12]

C. Monaco, J. Nanchahal, P. Taylor, M. Feldmann, Anti-TNF therapy: Past, present and

future, Int. Immunol. 27 (2015) 55–62. https://doi.org/10.1093/intimm/dxu102.

[13]

W. Ohashi, K. Hattori, Y. Hattori, Control of macrophage dynamics as a potential

therapeutic approach for clinical disorders involving chronic inflammation, J.

Pharmacol. Exp. Ther. 354 (2015) 240–250. https://doi.org/10.1124/jpet.115.225540.

[14]

I.G. Luzina, A.D. Keegan, N.M. Heller, G.A.W. Rook, T. Shea-Donohue, S.P. Atamas,

Regulation of inflammation by interleukin-4: a review of “alternatives,” J. Leukoc. Biol.

92 (2012) 753–764. https://doi.org/10.1189/jlb.0412214.

[15]

J.B. Allen, H.L. Wong, G.L. Costa, M.J. Bienkowski, S.M. Wahl, Suppression of

monocyte function and differential regulation of IL-1 and IL-1ra by IL-4 contribute to

resolution of experimental arthritis., J. Immunol. 151 (1993) 4344–51.

http://www.ncbi.nlm.nih.gov/pubmed/8409406.

[16]

K. Ghoreschi, P. Thomas, S. Breit, M. Dugas, R. Mailhammer, W. Van Eden, R. Van der

Zee, T. Biedermann, J. Prinz, M. Mack, U. Mrowietz, E. Christophers, D. Schlöndorff,

G. Plewig, C.A. Sander, M. Rocken, Interleukin-4 therapy of psoriasis induces Th2

responses and improves human autoimmune disease, Nat. Med. 9 (2003) 40–46.

https://doi.org/10.1038/nm804.

[17]

E. Lubberts, L.A.B. Joosten, M. Chabaud, L. Van Den Bersselaar, B. Oppers, C.J.J.

Coenen-De Roo, C.D. Richards, P. Miossec, W.B. Van Den Berg, IL-4 gene therapy for

collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents

bone erosion, J. Clin. Invest. 105 (2000) 1697–1710. https://doi.org/10.1172/JCI7739.

[18]

L.A.B. Joosten, E. Lubberts, P. Durez, M.M.A. Helsen, M.J.M. Jacobs, M. Goldman,

W.B. Van den Berg, Role of interleukin-4 and interleukin-10 in murine collagen-induced

arthritis: Protective effect of interleukin-4 and interleukin-10 treatment on cartilage

destruction, Arthritis Rheum. 40 (1997) 249–260.

https://doi.org/10.1002/art.1780400209.

[19]

L.A.B. Joosten, E. Lubberts, M.M.A. Helsen, T. Saxne, C.J.J. Coenen-De Roo, D.

Heinegård, W.B. Van Den Berg, Protection against cartilage and bone destruction by

systemic interleukin-4 treatment in established murine type II collagen-induced arthritis,

Arthritis Res. 1 (1999) 81–91. https://doi.org/10.1186/ar14.

48

[20]

E. Lubberts, L.A. Joosten, L. van Den Bersselaar, M.M. Helsen, A.C. Bakker, J.B. van

Meurs, F.L. Graham, C.D. Richards, W.B. van Den Berg, Adenoviral vector-mediated

overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents

cartilage destruction., J. Immunol. 163 (1999) 4546–56.

http://www.ncbi.nlm.nih.gov/pubmed/10510398.

[21]

J.Prendivill; N. Thatcher; M. Lind; R. McIntosh; A. Ghosh; P. Stern; D. Crowther,

Recombinant human interleukin-4 (rhu IL-4) administered by the intravenous and

subcutaneous routes in patients with advanced cancer—A phase I toxicity study and

pharmacokinetic analysis, Eur. J. Cancer. 29 (1993) 1700–1707.

[22]

J.A. Sosmon; S.G. Fisher; C.Kwfer; R.I.Fisher; T.M.Ellis, A phase I trial of continuous

infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL2) in cancer patients,

Ann. Oncol. (1994) 447–452.

[23]

J. Lundin, E. Kimby, L. Bergmann, T. Karakas, H. Mellstedt, A. Österborg, Interleukin 4

therapy for patients with chronic lymphocytic leukaemia: A phase I/II study, Br. J.

Haematol. 112 (2001) 155–160. https://doi.org/10.1046/j.1365-2141.2001.02525.x.

[24]

P. Dasgupta, A.D. Keegan, Contribution of alternatively activated macrophages to

allergic lung inflammation: A tale of mice and men, J. Innate Immun. 4 (2012) 478–488.

https://doi.org/10.1159/000336025.

[25]

H. Gandhi, R. Worch, K. Kurgonaite, M. Hintersteiner, P. Schwille, C. Bökel, T.

Weidemann, Dynamics and interaction of Interleukin-4 receptor subunits in living cells,

Biophys. J. 107 (2014) 2515–2527. https://doi.org/10.1016/j.bpj.2014.07.077.

[26]

K. Kurgonaite, H. Gandhi, T. Kurth, S. Pautot, P. Schwille, T. Weidemann, C. Bökel,

Essential role of endocytosis for interleukin-4-receptor-mediated JAK/STAT signalling,

J. Cell Sci. 128 (2015) 3781–3795. https://doi.org/10.1242/jcs.170969.

[27]

L.A. Mulcahy, R.C. Pink, D.R.F. Carter, Routes and mechanisms of extracellular vesicle

uptake, J. Extracell. Vesicles. 3 (2014) 1–14. https://doi.org/10.3402/jev.v3.24641.

[28]

K. Umemura, S. Ohtsuki, M. Nagaoka, K. Kusamori, T. Inoue, Y. Takahashi, Y.

Takakura, M. Nishikawa, Critical contribution of macrophage scavenger receptor 1 to

the uptake of nanostructured DNA by immune cells, Nanomedicine. (2021).

https://doi.org/10.1016/j.nano.2021.102386.

[29]

Y. Takahashi, M. Nishikawa, H. Shinotsuka, Y. Matsui, S. Ohara, T. Imai, Y. Takakura,

Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells

49

in mice after intravenous injection, J. Biotechnol. 165 (2013) 77–84.

https://doi.org/10.1016/j.jbiotec.2013.03.013.

[30]

C. Charoenviriyakul, Y. Takahashi, M. Morishita, M. Nishikawa, Y. Takakura, Role of

Extracellular Vesicle Surface Proteins in the Pharmacokinetics of Extracellular Vesicles,

Mol. Pharm. 15 (2018) 1073–1080. https://doi.org/10.1021/acs.molpharmaceut.7b00950.

[31]

M. Morishita, Y. Takahashi, A. Matsumoto, M. Nishikawa, Y. Takakura, Exosomebased tumor antigens–adjuvant co-delivery utilizing genetically engineered tumor cellderived exosomes with immunostimulatory CpG DNA, Biomaterials. 111 (2016) 55–65.

https://doi.org/10.1016/j.biomaterials.2016.09.031.

[32]

M. Morishita, Y. Takahashi, A. Matsumoto, M. Nishikawa, Y. Takakura, Exosomebased tumor antigens–adjuvant co-delivery utilizing genetically engineered tumor cellderived exosomes with immunostimulatory CpG DNA, Biomaterials. 111 (2016) 55–65.

https://doi.org/10.1016/j.biomaterials.2016.09.031.

[33]

D.G. You, G. Saravanakumar, S. Son, H.S. Han, R. Heo, K. Kim, I.C. Kwon, J.Y. Lee,

J.H. Park, Dextran sulfate-coated superparamagnetic iron oxide nanoparticles as a

contrast agent for atherosclerosis imaging, Carbohydr. Polym. 101 (2014) 1225–1233.

https://doi.org/10.1016/j.carbpol.2013.10.068.

[34]

D.C. Watson, D. Bayik, A. Srivatsan, C. Bergamaschi, A. Valentin, G. Niu, J. Bear, M.

Monninger, M. Sun, A. Morales-Kastresana, J.C. Jones, B.K. Felber, X. Chen, I. Gursel,

G.N. Pavlakis, Efficient production and enhanced tumor delivery of engineered

extracellular vesicles, Biomaterials. 105 (2016) 195–205.

https://doi.org/10.1016/j.biomaterials.2016.07.003.

[35]

D.B. Thompson, R. Villaseñor, B.M. Dorr, M. Zerial, D.R. Liu, Cellular uptake

mechanisms and endosomal trafficking of supercharged proteins, Chem. Biol. 19 (2012)

831–843. https://doi.org/10.1016/j.chembiol.2012.06.014.

[36]

J. Li, H.C. Hsu, J.D. Mountz, Managing macrophages in rheumatoid arthritis by reform

or removal, Curr. Rheumatol. Rep. 14 (2012) 445–454. https://doi.org/10.1007/s11926012-0272-4.

[37]

M. Mendt, K. Rezvani, E. Shpall, Mesenchymal stem cell-derived exosomes for clinical

use, Bone Marrow Transplant. 54 (2019) 789–792. https://doi.org/10.1038/s41409-0190616-z.

[38]

Hui Zhao; Qianwen; Zhenzhen Pan; Yang Bai; Zequn Li; Huiying Zhang; Qiu Zhang;

50

Chun Guo; Lining Zhang; Qun Wang, Exosomes From Adipose-Derived Stem Cells

Attenuate Adipose Inflammation and Obesity Through Polarizing M2 Macrophages and

Beiging in White Adipose Tissue, 67 (n.d.) 235–247.

[39]

H. Kim, S.Y. Wang, G. Kwak, Y. Yang, I.C. Kwon, S.H. Kim, Exosome-Guided

Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing, Adv. Sci.

6 (2019). https://doi.org/10.1002/advs.201900513.

[40]

Y. Yang, X. Hu, L. Cheng, W. Tang, W. Zhao, Y. Yang, J. Zuo, Periplocoside A

ameliorated type II collagen-induced arthritis in mice via regulation of the balance of

Th17/Treg cells, Int. Immunopharmacol. 44 (2017) 43–52.

https://doi.org/10.1016/j.intimp.2016.12.013.

[41]

S. Gordon, Alternative activation of macrophages, Nat. Rev. Immunol. 3 (2003) 23–35.

https://doi.org/10.1038/nri978.

[42]

R.L. Gieseck, M.S. Wilson, T.A. Wynn, Type 2 immunity in tissue repair and fibrosis,

Nat. Rev. Immunol. 18 (2018) 62–76. https://doi.org/10.1038/nri.2017.90.

[43]

N.J. Horwood, Macrophage Polarization and Bone Formation: A review, Clin. Rev.

Allergy Immunol. 51 (2016) 79–86. https://doi.org/10.1007/s12016-015-8519-2.

[44]

S. Chen, H. Liang, Y. Ji, H. Kou, C. Zhang, G. Shang, C. Shang, Z. Song, L. Yang, L.

Liu, Y. Wang, H. Liu, Curcumin Modulates the Crosstalk Between Macrophages and

Bone Mesenchymal Stem Cells to Ameliorate Osteogenesis, Front. Cell Dev. Biol. 9

(2021) 1–13. https://doi.org/10.3389/fcell.2021.634650.

[45]

C. Guder, S. Gravius, C. Burger, D.C. Wirtz, F.A. Schildberg, Osteoimmunology: A

Current Update of the Interplay Between Bone and the Immune System, Front.

Immunol. 11 (2020) 1–19. https://doi.org/10.3389/fimmu.2020.00058.

[46]

R.G. Baker, M.S. Hayden, S. Ghosh, NF-κB, inflammation, and metabolic disease, Cell

Metab. 13 (2011) 11–22. https://doi.org/10.1016/j.cmet.2010.12.008.

[47]

P. Viatour, M.P. Merville, V. Bours, A. Chariot, Phosphorylation of NF-κB and IκB

proteins: Implications in cancer and inflammation, Trends Biochem. Sci. 30 (2005) 43–

52. https://doi.org/10.1016/j.tibs.2004.11.009.

[48]

P.P. Tak, G.S. Firestein, NF-κB: A key role in inflammatory diseases, J. Clin. Invest.

107 (2001) 7–11. https://doi.org/10.1172/JCI11830.

[49]

N. Wang, H. Liang, K. Zen, Molecular mechanisms that influence the macrophage M1M2 polarization balance, Front. Immunol. 5 (2014) 1–9.

51

https://doi.org/10.3389/fimmu.2014.00614.

[50]

M.J. May, F. D’Acquisto, L.A. Madge, J. Glockner, J.S. Pober, S. Ghosh, Selective

inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with

the IκB kinase complex, Science (80-. ). 289 (2000) 1550–1554.

https://doi.org/10.1126/science.289.5484.1550.

[51]

M.J. May, R.B. Marienfeld, S. Ghosh, Characterization of the IκB-kinase NEMO

binding domain, J. Biol. Chem. 277 (2002) 45992–46000.

https://doi.org/10.1074/jbc.M206494200.

[52]

S. Ghosh, M. Karin, Missing pieces in the NF-κB puzzle, Cell. 109 (2002) 81–96.

https://doi.org/10.1016/S0092-8674(02)00703-1.

[53]

I. Stancovski, D. Baltimore, NF-κB Activation: The IκB Kinase Revealed?, Cell. 91

(1997) 299–302.

[54]

T. Huxford, G. Ghosh, A structural guide to proteins of the NF-kappaB signaling

module., Cold Spring Harb. Perspect. Biol. 1 (2009) 1–16.

https://doi.org/10.1101/cshperspect.a000075.

[55]

M. Karin, M. Delhase, The IκB kinase (IKK) and NF-κB: Key elements of

proinflammatory signalling, Semin. Immunol. 12 (2000) 85–98.

https://doi.org/10.1006/smim.2000.0210.

[56]

S. Dai, T. Hirayama, S. Abbas, Y. Abu-Amer, The IκB kinase (IKK) inhibitor, NEMObinding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory

arthritis, J. Biol. Chem. 279 (2004) 37219–37222.

https://doi.org/10.1074/jbc.C400258200.

[57]

S.W. Tas, M.J. Vervoordeldonk, N. Hajji, M.J. May, S. Ghosh, P.P. Tak, Local

treatment with the selective IκB kinase β inhibitor NEMO-binding domain peptide

ameliorates synovial inflammation, Arthritis Res. Ther. 8 (2006) 1–9.

https://doi.org/10.1186/ar1958.

[58]

W. Shibata, S. Maeda, Y. Hikiba, A. Yanai, T. Ohmae, K. Sakamoto, H. Nakagawa, K.

Ogura, M. Omata, Cutting Edge: The IκB Kinase (IKK) Inhibitor, NEMO-Binding

Domain Peptide, Blocks Inflammatory Injury in Murine Colitis, J. Immunol. 179 (2007)

2681–2685. https://doi.org/10.4049/jimmunol.179.5.2681.

[59]

D. Sun, Z. Xiaoying, X. Xiang, Y. Liu, S. Zhang, C. Liu, S. Barnes, W. Grizzle, D.

Miller, H.-G. Zhang, A Novel Nanoparticle Drug Delivery System: The Anti-

52

inflammatory Activity of Curcumin Is Enhanced When Encapsulated in Exosomes, Mol.

Ther. 18 (2010) 1606–1614.

[60]

M. Haney, N. Klyachko, Y. Zhao, R. Gupta, E. Plotnikova, Z. He, T. Patel, A. Piroyan,

M. Sokolsky, A. Kabanov, E. Batrakova, Exosomes as Drug Delivery Vehicles for

Parkinson’s Disease Therapy, J. Control. Release. 207 (2015) 18–30.

https://doi.org/10.1016/j.physbeh.2017.03.040.

[61]

D.E. Murphy, O.G. de Jong, M. Brouwer, M.J. Wood, G. Lavieu, R.M. Schiffelers, P.

Vader, Extracellular vesicle-based therapeutics: natural versus engineered targeting and

trafficking, Exp. Mol. Med. 51 (2019). https://doi.org/10.1038/s12276-019-0223-5.

[62]

Y. Arima, W. Liu, Y. Takahashi, M. Nishikawa, Y. Takakura, Effects of Localization of

Antigen Proteins in Antigen-Loaded Exosomes on Efficiency of Antigen Presentation,

Mol. Pharm. 16 (2019) 2309–2314. https://doi.org/10.1021/acs.molpharmaceut.8b01093.

[63]

C. Charoenviriyakul, Y. Takahashi, M. Morishita, M. Nishikawa, Y. Takakura, Role of

Extracellular Vesicle Surface Proteins in the Pharmacokinetics of Extracellular Vesicles,

Mol. Pharm. 15 (2018) 1073–1080. https://doi.org/10.1021/acs.molpharmaceut.7b00950.

[64]

Y. Hayakawa, S. Maeda, H. Nakagawa, Y. Hikiba, W. Shibata, K. Sakamoto, A. Yanai,

Y. Hirata, K. Ogura, S. Muto, A. Itai, M. Omata, Effectiveness of IκB kinase inhibitors

in murine colitis-associated tumorigenesis, J. Gastroenterol. 44 (2009) 935–943.

https://doi.org/10.1007/s00535-009-0098-7.

[65]

R.S. Jope, C.J. Yuskaitis, E. Beurel, Glycogen Synthase Kinase-3 (GSK3):

Inflammation, Diseases, and Therapeutics, Neurochem. Res. 32 (2007) 577–595.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1970866/pdf/nihms24923.pdf%0Ahttp:/

/www.ncbi.nlm.nih.gov/pubmed/16944320.

[66]

M. Maqbool, M. Mobashir, N. Hoda, Pivotal role of glycogen synthase kinase-3: A

therapeutic target for Alzheimer’s disease, Eur. J. Med. Chem. 107 (2016) 63–81.

https://doi.org/10.1016/j.ejmech.2015.10.018.

[67]

M.A. Bogoyevitch, I. Boehm, A. Oakley, A.J. Ketterman, R.K. Barr, Targeting the JNK

MAPK cascade for inhibition: Basic science and therapeutic potential, Biochim.

Biophys. Acta - Proteins Proteomics. 1697 (2004) 89–101.

https://doi.org/10.1016/j.bbapap.2003.11.016.

[68]

B. Hu, L. Xu, Y. Li, X. Bai, M. Xing, Q. Cao, H. Liang, S. Song, A. Ji, A Peptide

Inhibitor of Macrophage Migration in Atherosclerosis Purified From the Leech

53

Whitmania Pigra, J. Ethnopharmacol. (2020). https://doi.org/10.1016/j.jep.2020.112723.

[69]

M.N. Rahimi, L.K. Buckton, S.S. Zaiter, J. Kho, V. Chan, A. Guo, J. Konesan, S. Kwon,

L.K.O. Lam, M.F. Lawler, M. Leong, G.D. Moldovan, D.A. Neale, G. Thornton, S.R.

McAlpine, Synthesis and Structure-Activity Relationships of Inhibitors That Target the

C-Terminal MEEVD on Heat Shock Protein 90, ACS Med. Chem. Lett. 9 (2018) 73–77.

https://doi.org/10.1021/acsmedchemlett.7b00310.

[70]

M.N. Rahimi, S.R. McAlpine, Protein-protein inhibitor designed de novo to target the

MEEVD region on the C-terminus of Hsp90 and block co-chaperone activity, Chem.

Commun. 55 (2019) 846–849. https://doi.org/10.1039/C8CC07576J.

[71]

S. Sueda, Y.Q. Li, H. Kondo, Y. Kawarabayasi, Substrate specificity of archaeon

Sulfolobus tokodaii biotin protein ligase, Biochem. Biophys. Res. Commun. 344 (2006)

155–159. https://doi.org/10.1016/j.bbrc.2006.03.118.

[72]

S. Sueda, S. Yoneda, H. Hayashi, Site-Specific Labeling of Proteins by Using Biotin

Protein Ligase Conjugated with Fluorophores, ChemBioChem. 12 (2011) 1367–1375.

https://doi.org/10.1002/cbic.201000738.

[73]

S. Suman, P.K. Sharma, G. Rai, S. Mishra, D. Arora, P. Gupta, Y. Shukla, Current

perspectives of molecular pathways involved in chronic inflammation-mediated breast

cancer, Biochem. Biophys. Res. Commun. 472 (2016) 401–409.

https://doi.org/10.1016/j.bbrc.2015.10.133.

[74]

Q. Wu, W. Zhou, S. Yin, Y. Zhou, T. Chen, J. Qian, R. Su, L. Hong, H. Lu, F. Zhang, H.

Xie, L. Zhou, S. Zheng, Blocking Triggering Receptor Expressed on Myeloid Cells-1Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses

Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver

Cancer, Hepatology. 70 (2019) 198–214. https://doi.org/10.1002/hep.30593.

[75]

A.N. Chamseddine, T. Assi, O. Mir, S. Chouaib, Modulating tumor-associated

macrophages to enhance the efficacy of immune checkpoint inhibitors: A TAM-pting

approach, Pharmacol. Ther. 231 (2022) 107986.

https://doi.org/10.1016/j.pharmthera.2021.107986.

[76]

D.G. DeNardo, B. Ruffell, Macrophages as regulators of tumour immunity and

immunotherapy, Nat. Rev. Immunol. 19 (2019) 369–382.

https://doi.org/10.1038/s41577-019-0127-6.

[77]

Y.R. Na, J.W. Kwon, D.Y. Kim, H. Chung, J. Song, D. Jung, H. Quan, D. Kim, J.S.

54

Kim, Y.W. Ju, W. Han, H.S. Ryu, Y.S. Lee, J.J. Hong, S.H. Seok, Protein Kinase A

Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of

Macrophages, Cell Rep. 31 (2020) 107643.

https://doi.org/10.1016/j.celrep.2020.107643.

[78]

K. Takaishi, Y. Komohara, H. Tashiro, H. Ohtake, T. Nakagawa, H. Katabuchi, M.

Takeya, Involvement of M2-polarized macrophages in the ascites from advanced

epithelial ovarian carcinoma in tumor progression via Stat3 activation, Cancer Sci. 101

(2010) 2128–2136. https://doi.org/10.1111/j.1349-7006.2010.01652.x.

[79]

C. Liu, P. Ke, J. Zhang, X. Zhang, X. Chen, Protein Kinase Inhibitor Peptide as a Tool to

Specifically Inhibit Protein Kinase A, Front. Physiol. 11 (2020).

https://doi.org/10.3389/fphys.2020.574030.

[80]

U. Bharadwaj, M.M. Kasembeli, D.J. Tweardy, STAT3 Inhibitors in Cancer: A

Comprehensive Update, 2016. https://doi.org/10.1007/978-3-319-42949-6_5.

[81]

N. Takiguchi, Y. Takahashi, M. Nishikawa, Y. Matsui, Y. Fukuhara, D. Oushiki, K.

Kiyose, K. Hanaoka, T. Nagano, Y. Takakura, Positive correlation between the

generation of reactive oxygen species and activation/reactivation of transgene expression

after hydrodynamic injections into mice, Pharm. Res. 28 (2011) 702–711.

https://doi.org/10.1007/s11095-010-0331-3.

55

...