ABSTRACT BACKGROUND Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23

(CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 (CCR1). However, the effect of CCL23 on other immune cells in the TME is unknown. METHODS CCL23 levels were measured by

ELISA. The expression of surface markers in exhaustion assays was quantified by flow cytometry. Signalling pathways were identified by phosphokinase array and validated by western blot.

RESULTS Ascites from patients with high-grade serous ovarian cancer (HGSC) contain high levels of CCL23. Similarly, significantly higher CCL23 levels were found in plasma from HGSC patients

induced upregulation of immune checkpoint proteins on CD8 + T cells, including CTLA-4, TIGIT, TIM-3 and LAG-3 via phosphorylation of GSK3β in CD8 + T cells. CONCLUSIONS Our data suggest that

CCL23 produced by macrophages contributes to the immune-suppressive TME in ovarian cancer by inducing an exhausted T-cell phenotype. Access through your institution Buy or subscribe This is

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HYPERINFLAMMATORY REPOLARISATION OF OVARIAN CANCER PATIENT MACROPHAGES BY ANTI-TUMOUR IGE ANTIBODY, MOV18, RESTRICTS AN IMMUNOSUPPRESSIVE MACROPHAGE:TREG CELL INTERACTION Article Open access

10 April 2025 SINGLE-CELL ANALYSES IMPLICATE ASCITES IN REMODELING THE ECOSYSTEMS OF PRIMARY AND METASTATIC TUMORS IN OVARIAN CANCER Article Open access 24 July 2023 FGL2 PROMOTES TUMOUR

GROWTH AND ATTENUATES INFILTRATION OF ACTIVATED IMMUNE CELLS IN MELANOMA AND OVARIAN CANCER MODELS Article Open access 08 January 2024 DATA AVAILABILITY RNA-seq data for patients with

ovarian cancer were retrieved from TCGA, which is publicly available at https://portal.gdc.cancer.gov/. REFERENCES * Wang Y, Ren F, Song Z, Wang X, Zhang C, Ouyang L. PARP inhibitors in

patients with newly diagnosed advanced ovarian cancer: a meta-analysis of randomized clinical trials. Front Oncol. 2020;10:1204. Article  PubMed  PubMed Central  Google Scholar  * Borella F,

Ghisoni E, Giannone G, Cosma S, Benedetto C, Valabrega G, et al. Immune checkpoint inhibitors in epithelial ovarian cancer: an overview on efficacy and future perspectives. Diagnostics.

2020;10:146. Article  CAS  PubMed Central  Google Scholar  * Rodriguez GM, Galpin KJC, McCloskey CW, Vanderhyden BC. The tumor microenvironment of epithelial ovarian cancer and its influence

on response to immunotherapy. Cancers. 2018;10:E242. Article  PubMed  CAS  Google Scholar  * Jimenez-Sanchez A, Memon D, Pourpe S, Veeraraghavan H, Li Y, Vargas HA, et al. Heterogeneous

tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell. 2017;170:927–38. e20 Article  CAS  PubMed  PubMed Central  Google Scholar  *

Krishnan V, Schaar B, Tallapragada S, Dorigo O. Tumor associated macrophages in gynecologic cancers. Gynecol Oncol. 2018;149:205–13. Article  CAS  PubMed  Google Scholar  * Petty AJ, Yang Y.

Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy. 2017;9:289–302. Article  CAS  PubMed  PubMed Central  Google Scholar  * Xiang X, Wang J, Lu D, Xu X.

Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther. 2021;6:75. Article  PubMed  PubMed Central  Google Scholar  * Zhang M, He Y, Sun X, Li

Q, Wang W, Zhao A, et al. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res. 2014;7:19. Article  PubMed  CAS 

PubMed Central  Google Scholar  * Dun EC, Hanley K, Wieser F, Bohman S, Yu J, Taylor RN. Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments

of endometrial carcinomas. Int J Gynecol Pathol. 2013;32:576–84. Article  CAS  PubMed  Google Scholar  * Petrillo M, Zannoni GF, Martinelli E, Pedone Anchora L, Ferrandina G, Tropeano G, et

al. Polarisation of tumor-associated macrophages toward M2 phenotype correlates with poor response to chemoradiation and reduced survival in patients with locally advanced cervical cancer.

PLoS ONE. 2015;10:e0136654. Article  PubMed  CAS  PubMed Central  Google Scholar  * Krishnan V, Tallapragada S, Schaar B, Kamat K, Chanana AM, Zhang Y, et al. Omental macrophages secrete

chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1. Commun Biol. 2020;3:524. Article  CAS  PubMed  PubMed Central  Google Scholar  * Poposki JA, Uzzaman A,

Nagarkar DR, Chustz RT, Peters AT, Suh LA, et al. Elevated expression of CC Chemokine ligand 23 in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol.

2011;128:73–81. e4 Article  CAS  PubMed  PubMed Central  Google Scholar  * Arruda-Silva F, Bianchetto-Aguilera F, Gasperini S, Polletti S, Cosentino E, Tamassia N, et al. Human neutrophils

produce CCL23 in response to various TLR-agonists and TNFα. Front Cell Infect Microbiol. 2017;7:176. * Novak H, Müller A, Harrer N, Günther C, Carballido JM, Woisetschläger M. CCL23

expression is induced by IL-4 in a STAT6-dependent fashion. J Immunol. 2007;178:4335–41. Article  CAS  PubMed  Google Scholar  * Cheng JF, Jack R. CCR1 antagonists. Mol Divers.

2008;12:17–23. Article  CAS  PubMed  Google Scholar  * Rabin RL, Park MK, Liao F, Swofford R, Stephany D, Farber JM. Chemokine receptor responses on T cells are achieved through regulation

of both receptor expression and signaling. J Immunol. 1999;162:3840–50. CAS  PubMed  Google Scholar  * Hwang J, Son KN, Kim CW, Ko J, Na DS, Kwon BS, et al. Human CC chemokine CCL23, a

ligand for CCR1, induces endothelial cell migration and promotes angiogenesis. Cytokine. 2005;30:254–63. Article  CAS  PubMed  Google Scholar  * Foroughi F, Amirzargar A, Ahmadpoor P,

Noorbakhsh F, Nafar M, Yekaninejad MS, et al. Increased levels of CD4(+) and CD8(+) T cells expressing CCR1 in patients developing allograft dysfunction; a cohort study. Transpl Immunol.

2016;38:67–74. Article  CAS  PubMed  Google Scholar  * Conroy MJ, Galvin KC, Kavanagh ME, Mongan AM, Doyle SL, Gilmartin N, et al. CCR1 antagonism attenuates T cell trafficking to omentum

and liver in obesity-associated cancer. Immunol Cell Biol. 2016;94:531–7. Article  CAS  PubMed  Google Scholar  * Kim J, Kim YS, Ko J. CKβ8/CCL23 and its isoform CKβ8-1 induce up-regulation

of cyclins via the Gi/Go protein/PLC/PKCδ/ERK leading to cell-cycle progression. Cytokine. 2010;50:42–9. Article  CAS  PubMed  Google Scholar  * Son KN, Hwang J, Kwon BS, Kim J. Human CC

chemokine CCL23 enhances expression of matrix metalloproteinase-2 and invasion of vascular endothelial cells. Biochem Biophys Res Commun. 2006;340:498–504. Article  CAS  PubMed  Google

Scholar  * Han KY, Kim CW, Lee TH, Son Y, Kim J. CCL23 up-regulates expression of KDR/Flk-1 and potentiates VEGF-induced proliferation and migration of human endothelial cells. Biochem

Biophys Res Commun. 2009;382:124–8. Article  CAS  PubMed  Google Scholar  * Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F, et al. Determining cell type abundance and

expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019;37:773–82. Article  CAS  PubMed  PubMed Central  Google Scholar  * Taylor A, Harker JA, Chanthong K, Stevenson PG,

Zuniga EI, Rudd CE. Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8(+) cytolytic T cell responses. Immunity. 2016;44:274–86.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J

Hematol Oncol. 2019;12:76. Article  PubMed  PubMed Central  Google Scholar  * Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in

ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9. Article  CAS  PubMed  Google Scholar  * Zhou J, Tang Z, Gao S, Li C, Feng Y, Zhou X.

Tumor-associated macrophages: recent insights and therapies. Front Oncol. 2020;10:188. Article  PubMed  PubMed Central  Google Scholar  * Cao Q, Wang Y, Zheng D, Sun Y, Wang Y, Lee VW, et

al. IL-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis. J Am Soc Nephrol. 2010;21:933–42. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells.

Immunology. 2006;117:433–42. Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor

progression. J Biomed Sci. 2019;26:78. Article  PubMed  CAS  PubMed Central  Google Scholar  * Wang D, Yang L, Yue D, Cao L, Li L, Wang D, et al. Macrophage-derived CCL22 promotes an

immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion. Cancer Lett. 2019;452:244–53. Article  CAS  PubMed  Google Scholar  * Reinartz S, Schumann T, Finkernagel F,

Wortmann A, Jansen JM, Meissner W, et al. Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and

early relapse. Int J Cancer. 2014;134:32–42. Article  PubMed  CAS  Google Scholar  * Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not

pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis. 2014;17:109–18. Article  CAS  PubMed  Google Scholar  * Votta BJ, White JR, Dodds RA, James IE, Connor JR,

Lee-Rykaczewski E, et al. CKbeta-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues. J Cell Physiol. 2000;183:196–207. Article 

CAS  PubMed  Google Scholar  * Shih CH, van Eeden SF, Goto Y, Hogg JC. CCL23/myeloid progenitor inhibitory factor-1 inhibits production and release of polymorphonuclear leukocytes and

monocytes from the bone marrow. Exp Hematol. 2005;33:1101–8. Article  CAS  PubMed  Google Scholar  * Kim J, Kim YS, Ko J. CK beta 8/CCL23 induces cell migration via the Gi/Go protein/PLC/PKC

delta/NF-kappa B and is involved in inflammatory responses. Life Sci. 2010;86:300–8. Article  CAS  PubMed  Google Scholar  * Rioja I, Hughes FJ, Sharp CH, Warnock LC, Montgomery DS, Akil M,

et al. Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor alpha, tumor necrosis factor receptor superfamily member 9,

and macrophage colony-stimulating factor. Arthritis Rheum. 2008;58:2257–67. Article  CAS  PubMed  Google Scholar  * Castillo L, Rohatgi A, Ayers CR, Owens AW, Das SR, Khera A, et al.

Associations of four circulating chemokines with multiple atherosclerosis phenotypes in a large population-based sample: results from the Dallas heart study. J Interferon Cytokine Res.

2010;30:339–47. Article  CAS  PubMed  PubMed Central  Google Scholar  * Poposki JA, Uzzaman A, Nagarkar DR, Chustz RT, Peters AT, Suh LA, et al. Increased expression of the chemokine CCL23

in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2011;128:73–81. Article  CAS  PubMed  PubMed Central  Google Scholar  * Yanaba K, Yoshizaki A, Muroi E,

Ogawa F, Asano Y, Kadono T, et al. Serum CCL23 levels are increased in patients with systemic sclerosis. Arch Dermatol Res. 2011;303:29–34. Article  CAS  PubMed  Google Scholar  * Simats A,

Garcia-Berrocoso T, Penalba A, Giralt D, Llovera G, Jiang Y, et al. CCL23: a new CC chemokine involved in human brain damage. J Intern Med. 2018;283:461–75. Article  CAS  PubMed  Google

Scholar  * Steele L, Mannion AJ, Shaw G, Maclennan KA, Cook GP, Rudd CE, et al. Non-redundant activity of GSK-3α and GSK-3β in T cell-mediated tumor rejection. iScience. 2021;24:102555.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Rudd CE, Chanthong K, Taylor A. Small Molecule Inhibition of GSK-3 Specifically Inhibits the Transcription of Inhibitory Co-receptor

LAG-3 for Enhanced Anti-tumor Immunity. Cell Rep. 2020;30:2075–82. Article  CAS  PubMed  Google Scholar  * Baitsch L, Baumgaertner P, Devêvre E, Raghav SK, Legat A, Barba L, et al.

Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest. 2011;121:2350–60. Article  CAS  PubMed  PubMed Central  Google Scholar  * Thommen DS, Schreiner

J, Müller P, Herzig P, Roller A, Belousov A, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors.

Cancer Immunol Res. 2015;3:1344–55. Article  CAS  PubMed  Google Scholar  * Balança C-C, Salvioni A, Scarlata C-M, Michelas M, Martinez-Gomez C, Gomez-Roca C, et al. PD-1 blockade restores

helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells. JCI Insight. 2021;6:142513. Article  PubMed  Google Scholar  * Foord E, Klynning C, Schoutrop E, Förster JM, Krieg

J, Mörtberg A, et al. Profound functional suppression of tumor-infiltrating T-cells in ovarian cancer patients can be reversed using PD-1-blocking antibodies or DARPin® proteins. J Immunol

Res. 2020;2020:e7375947. Article  CAS  Google Scholar  * Zhang AW, McPherson A, Milne K, Kroeger DR, Hamilton PT, Miranda A, et al. Interfaces of malignant and immunologic clonal dynamics in

ovarian cancer. Cell 2018;173:1755–69. e22 Article  CAS  PubMed  Google Scholar  * Olalekan S, Xie B, Back R, Eckart H, Basu A. Characterizing the tumor microenvironment of metastatic

ovarian cancer by single-cell transcriptomics. Cell Rep. 2021;35:109165. Article  CAS  PubMed  Google Scholar  Download references FUNDING This work was supported by the Mary Lake Polan

Gynecologic Oncology Endowment for Research (OD), the Vivian Scott Fellowship in Gynecologic Oncology (OD). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Obstetrics and

Gynecology, Division of Gynecologic Oncology, Stanford Women’s Cancer Center, Stanford Cancer Institute, Stanford, CA, USA Kalika Kamat, Venkatesh Krishnan & Oliver Dorigo Authors *

Kalika Kamat View author publications You can also search for this author inPubMed Google Scholar * Venkatesh Krishnan View author publications You can also search for this author inPubMed 

Google Scholar * Oliver Dorigo View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS KK, VK and OD designed experiments; KK carried out and

analyzed experiments; KK, VK and OD prepared the figures and wrote the initial draft of the manuscript; all authors edited the manuscript; VK and OD provided supervision. CORRESPONDING

AUTHOR Correspondence to Oliver Dorigo. ETHICS DECLARATIONS COMPETING INTERESTS KK and VK have no competing interests. OD has served on Advisory Boards for Merck, Eisai, PACT, GSK, IMV,

Genentech. OD received funding for clinical research from AstraZeneca, IMV, Millenium, Pharmamar, Genentech, Bioeclipse. ETHICS APPROVAL AND CONSENT TO PARTICIPATE Patient samples were

collected under an approved Institutional Review Board (IRB) protocol at Stanford University and the University of Pennsylvania. Informed consent for healthy plasma was obtained by

Innovative Research (Novi, MI). This study was performed in accordance with the Declaration of Helsinki. CONSENT TO PUBLISH Not applicable. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

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O. Macrophage-derived CCL23 upregulates expression of T-cell exhaustion markers in ovarian cancer. _Br J Cancer_ 127, 1026–1033 (2022). https://doi.org/10.1038/s41416-022-01887-3 Download

citation * Received: 15 December 2021 * Revised: 16 May 2022 * Accepted: 07 June 2022 * Published: 24 June 2022 * Issue Date: 05 October 2022 * DOI:

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