Cited by 875Chemokine receptors and signalingCancer Immunotherapy and BiomarkersImmune cells in cancer

Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

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Dangaj, Denarda, Bruand, Marine, Grimm, Alizée J., Ronet, Catherine, Barras, David, Duttagupta, Priyanka A., Lanitis, Evripidis, Duraiswamy, Jaikumar +19 more·2019·Cancer Cell

Abstract

We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

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Crossref · 10.1016/j.ccell.2019.05.004

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  • CXCL10 and CCL5 are dominant mediators for recruitment of CXCR3+ and CCR5+ tumor-specific T lymphocytes into tumors, and their intratumoral expression correlates with favorable clinical outcomes in melanoma.

    “These chemokines have been identified as the dominant mediators for the recruitment of CXCR3+ and CCR5+ tumor-specific T lymphocytes into the tumors and their intratumoral expression correlated with favorable clinical outcomes in patients with melanoma30–32.”

    From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [32]

    The Introduction links CXCL10 and CCL5 to T-cell infiltration in melanoma and describes the importance of CXCR3 and CCR5 on tumor-infiltrating lymphocytes. However, the Results identify CCL5 and CXCL9—not CXCL10—as the key pair associated with T-cell engraftment and longer survival in melanoma. Section labels are available in our copy, but page numbers are not. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • Together with CXCL9, CXCL10 is a dominant chemokine for the recruitment of tumor-specific CD8+ T cells into tumors.

    “Together with CXCL9, another CXCR3-binding chemokine, CXCL10 is a dominant chemokine for the recruitment of tumor-specific CD8+ T cells into the tumors31,32.”

    From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [32]

    The Results and Discussion link CXCL9 to CD8+ T-cell infiltration and T-cell recruitment. The Discussion says CXCL10 may have a complementary role, but that CXCL10 expression does not correlate closely with CD8+ infiltration and may not translate to effective infiltration. The paper therefore does not support calling CXCL10 a dominant recruitment chemokine alongside CXCL9. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Research works printed but not linked: 43

  1. Angelova M, Mlecnik B, Vasaturo A, Bindea G, Fredriksen T, Lafontaine L, Buttard B, Morgand E, Bruni D, Jouret-Mourin A, (2018). Evolution of Metastases in Space and Time under Immune Selection. Cell 175, 751– 765 e716. 30318143
  2. Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, Ascierto ML, De Giorgi V, Liu Q, Delogu LG, (2013). CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. Br J Cancer 109, 2412– 2423. 24129241 PMC3817317
  3. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, (2013). Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782– 795. 24138885
  4. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, Katsaros D, O’Brien-Jenkins A, Gimotty PA, and Coukos G (2008). Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14, 28– 36. 18157142
  5. Burke SJ, Goff MR, Lu D, Proud D, Karlstad MD, and Collier JJ (2013). Synergistic expression of the CXCL10 gene in response to IL-1beta and IFN-gamma involves NF-kappaB, phosphorylation of STAT1 at Tyr701, and acetylation of histones H3 and H4. J Immunol 191, 323– 336. 23740952
  6. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, Hackl H, and Trajanoski Z (2017). Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade. Cell reports 18, 248– 262. 28052254
  7. Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, Miller JP, Bassett RL, Gopalakrishnan V, Wani K, (2016). Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. Cancer Discov 6, 827– 837. 27301722 PMC5082984
  8. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10, 942– 949. 15322536
  9. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, (2002). Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850– 854. 12242449 PMC1764179
  10. Duraiswamy J, Freeman GJ, and Coukos G (2013). Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res 73, 6900– 6912. 23975756 PMC3851914
  11. Farber JM (1990). A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines. Proc Natl Acad Sci U S A 87, 5238– 5242. 2115167 PMC54298
  12. Farber JM (1993). HuMig: a new human member of the chemokine family of cytokines. Biochem Biophys Res Commun 192, 223– 230. 8476424
  13. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, (2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960– 1964. 17008531
  14. Ganzfried BF, Riester M, Haibe-Kains B, Risch T, Tyekucheva S, Jazic I, Wang XV, Ahmadifar M, Birrer MJ, Parmigiani G, (2013). curatedOvarianData: clinically annotated data for the ovarian cancer transcriptome. Database (Oxford) 2013, bat013. PMC3625954 23550061
  15. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, (2015). Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372, 2018– 2028. 25891174
  16. Gonzalez-Martin A, Gomez L, Lustgarten J, Mira E, and Manes S (2011). Maximal T cell-mediated antitumor responses rely upon CCR5 expression in both CD4(+) and CD8(+) T cells. Cancer Res 71, 5455– 5466. 21715565
  17. Gooden MJ, de Bock GH, Leffers N, Daemen T, and Nijman HW (2011). The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105, 93– 103. 21629244 PMC3137407
  18. Griffith JW, Sokol CL, and Luster AD (2014). Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 32, 659– 702. 24655300
  19. Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, (2016). Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell 29, 587– 601. 27070705
  20. Herwig R, Hardt C, Lienhard M, and Kamburov A (2016). Analyzing and interpreting genome data at the network level with ConsensusPathDB. Nat Protoc 11, 1889– 1907. 27606777
  21. Hong M, Puaux AL, Huang C, Loumagne L, Tow C, Mackay C, Kato M, Prevost-Blondel A, Avril MF, Nardin A, and Abastado JP (2011). Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res 71, 6997– 7009. 21948969
  22. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, and Coukos G (2012). Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol 124, 192– 198. 22040834 PMC3298445
  23. Kamburov A, Stelzl U, Lehrach H, and Herwig R (2013). The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res 41, D793– 800. 23143270 PMC3531102
  24. Karonitsch T, von Dalwigk K, Steiner CW, Bluml S, Steiner G, Kiener HP, Smolen JS, and Aringer M (2012). Interferon signals and monocytic sensitization of the interferon-gamma signaling pathway in the peripheral blood of patients with rheumatoid arthritis. Arthritis Rheum 64, 400– 408. 21953607
  25. Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, and Gillitzer R (1999). Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J Pathol 189, 552– 558. 10629557
  26. Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, (2014). Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5, 587– 598. 24583822 PMC3996658
  27. Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, Richman LP, Lin JH, Sun YH, Rech AJ, (2018). Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. Immunity 49, 178– 193 e177. 29958801 PMC6707727
  28. Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, and Jones PA (2009). DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 8, 1579– 1588. 19509260 PMC3186068
  29. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, and Coukos G (2014). Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20, 607– 615. 24793239 PMC4060245
  30. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, and Alizadeh AA (2015). Robust enumeration of cell subsets from tissue expression profiles. Nature methods 12, 453– 457. 25822800 PMC4739640
  31. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, (2015). Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249– 253. 26503055 PMC4779053
  32. Rodig SJ, Gusenleitner D, Jackson DG, Gjini E, Giobbie-Hurder A, Jin C, Chang H, Lovitch SB, Horak C, Weber JS, (2018). MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci Transl Med 10. 30021886
  33. Sanchez-Paulete AR, Cueto FJ, Martinez-Lopez M, Labiano S, Morales-Kastresana A, Rodriguez-Ruiz ME, Jure-Kunkel M, Azpilikueta A, Aznar MA, Quetglas JI, (2016). Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells. Cancer Discov 6, 71– 79. 26493961 PMC5036540
  34. Schlienger K, Craighead N, Lee KP, Levine BL, and June CH (2000). Efficient priming of protein antigen-specific human CD4(+) T cells by monocyte-derived dendritic cells. Blood 96, 3490– 3498. 11071646
  35. Spranger S, Bao R, and Gajewski TF (2015). Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231– 235. 25970248
  36. Velasco-Velazquez M, Xolalpa W, and Pestell RG (2014). The potential to target CCL5/CCR5 in breast cancer. Expert Opin Ther Targets 18, 1265– 1275. 25256399
  37. Viola A, Sarukhan A, Bronte V, and Molon B (2012). The pros and cons of chemokines in tumor immunology. Trends Immunol 33, 496– 504. 22726608
  38. Westergaard MCW, Andersen R, Chong C, Kjeldsen JW, Pedersen M, Friese C, Hasselager T, Lajer H, Coukos G, Bassani-Sternberg M, (2019). Tumour-reactive T cell subsets in the microenvironment of ovarian cancer. Br J Cancer PMC6461863 30718808
  39. Ye Q, Song DG, Poussin M, Yamamoto T, Best A, Li C, Coukos G, and Powell DJ Jr. (2014). CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res 20, 44– 55. 24045181 PMC3947326
  40. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, (2016). Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med 375, 819– 829. 27433843 PMC5007206
  41. Zhai Y, Shen XD, Gao F, Zhao A, Freitas MC, Lassman C, Luster AD, Busuttil RW, and Kupiec-Weglinski JW (2008). CXCL10 regulates liver innate immune response against ischemia and reperfusion injury. Hepatology 47, 207– 214. 18041715
  42. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, (2003). Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348, 203– 213. 12529460
  43. Zsiros E, Duttagupta P, Dangaj D, Li H, Frank R, Garrabrant T, Hagemann IS, Levine BL, June CH, Zhang L, (2015). The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy. Clin Cancer Res 21, 2840– 2850. 25712684 PMC4987088

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Authors
Dangaj, D., Bruand, M., Grimm, A. J., Ronet, C., Barras, D., Duttagupta, P. A., Lanitis, E., Duraiswamy, J., Tanyi, J. L., Benencia, F., Conejo-Garcia, J., Ramay, H. R., Montone, K. T., Powell, D. J., Gimotty, P. A., Facciabene, A., Jackson, D. G., Weber, J. S., Rodig, S. J., Hodi, S. F., Kandalaft, L. E., Irving, M., Zhang, L., Foukas, P., Rusakiewicz, S., Delorenzi, M., & Coukos, G.
Affiliations
  • Ludwig Cancer Research (CH)
  • SIB Swiss Institute of Bioinformatics (CH)
  • University of Chicago (US)
  • Center for Biologics Evaluation and Research (US)
  • University of Pennsylvania (US)
  • Moffitt Cancer Center (US)
  • Bristol-Myers Squibb (United States) (US)
  • NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
  • Brigham and Women's Hospital (US)
  • Dana-Farber Cancer Institute (US)
  • National and Kapodistrian University of Athens (GR)
Corresponding author
Coukos, George
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2019-06
Volume
35
Issue
6
Pages
885-900.e10
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2949498852
Cited by
875
References
11
Citations by year
2026: 97 · 2025: 123 · 2024: 162 · 2023: 141 · 2022: 154 · 2021: 122 · 2020: 67 · 2019: 9
FWCI
38.35
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • AstraZeneca
  • Ludwig Institute for Cancer Research
  • Genentech
  • Sidney Kimmel Foundation
  • GlaxoSmithKline
  • Neos Therapeutics
  • Merck
  • Boehringer Ingelheim
  • Bristol-Myers Squibb
  • Takeda Pharmaceutical Company
  • Gilead Sciences (20100111973)
  • Astellas Pharma
  • Celgene
  • AbbVie
  • Amgen
  • University of Pennsylvania Health System
  • Novartis
  • Daiichi-Sankyo
  • Roche
  • Eisai
Topics
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
RANTES, CXCL9, T cell infiltration, tumor-infiltrating lymphocytes, interferon-gamma, myeloid cells, CXCR3 ligands, DNA methylation, epigenetic silencing, immune checkpoint blockade, tumor surveillance, solid tumors
MeSH terms
Antineoplastic Agents, Immunological, Animals, Chemotaxis, Leukocyte, Dendritic Cells, Female, Humans, Immunotherapy, Interferon-gamma, Lymphocyte Activation, Macrophages, Mice, Inbred C57BL, Ovarian Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Cytokines, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Coculture Techniques, Chemokine CCL5, DNA Methylation, Paracrine Communication, Epigenesis, Genetic, Cell Line, Tumor, Receptors, CXCR3, Chemokine CXCL9

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