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Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell Recruitment
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Abstract
Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.
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“Tumors from patients showing sustained treatment response predominately demonstrate a T cell-inflamed tumor microenvironment prior to, or early on, treatment.”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [6]
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“an effector population shown to be a target of downstream STING signaling involving the IFN-β-CXCL9/10 axis.54–58”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [55]
Experimental — accuracy not yet measuredIn the citing paper
“Tumor analysis from patients with metastatic melanoma receiving vaccine and cytokine therapies suggested a paradigm of two broad phenotypes characterized by the presence or absence a T cell-inflamed tumor.”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [6]
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“Activation of cGAS and STING has also been linked to age-related macular degeneration (Kerur et al. 2018) and liver fibrosis (Iracheta-Vellve et al. 2016).”
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BackgroundOvercoming Barriers in Oncolytic Virotherapy with HDAC Inhibitors and Immune Checkpoint Blockade
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“Moreover, a deficiency in appropriate T cell-attracting chemokines, such as CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10, may contribute to the inefficient trafficking of effector T cells into the tumour bed [43].”
BackgroundInhibition of PI3K pathway increases immune infiltrate in muscle-invasive bladder cancer
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“Moreover, a panel of chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was described to be expressed in metastatic melanomas rich in infiltrating T-cells.(8) These results are in accordance with the upregulated chemokine transcripts that we detected after inhibition of the PI3K pathway.”
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“For instance, elevated levels of CXCL8/IL-8 in the melanoma microenvironment [188] can be harnessed by engineering T cells to overexpress the matching chemokine receptor CXCR2 (Figure 3c).”
BackgroundCytotoxic T cells swarm by homotypic chemokine signalling
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“Gene expression analysis of human melanoma metastases identified three subsets of melanomas: type 1, characterized by immune signatures, and types 2 and 3 both lacking immune signatures.(6) Group 2 tumors clustered more closely to Group 1 but had low expression of most immune signature genes.”
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“For instance, secretion of endothelial factors and chemokines by tumor cells has been deemed responsible for this phenotype in various cancer models [27,105-107].”
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BackgroundInfluentialLymphatic Vessels, Inflammation, and Immunity in Skin Cancer
Lund, A. W., Medler, T. R., Leachman, S. A., & Coussens, L. M. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0023 · Cited by 97
“Melanoma was one of the first tumors to be associated with spontaneous antitumor immunity leading to regression—appearance of autoimmune vitiligo (139), presence of intralesional tumor-infiltrating lymphocytes (140), expression of lymphocyte chemotactic factors (141), and a type I IFN transcriptional profile (142) enr…”
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Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist
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Determinants of response and resistance to CAR T cell therapy
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Chemokine networks modulating natural killer cell trafficking to solid tumors
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“In the setting of cancer, preferential migration of immune cells to tumor sites is mediated by tumor-secreted chemoattractants such as CCL2, CXCL9, CXCL10, and CXCL11 (65).”
BackgroundInfluentialCombining chemotherapy with CAR-T cell therapy in treating solid tumors
Wang, A. X., Ong, X., D’Souza, C., Neeson, P. J., & Zhu, J. J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1140541 · Cited by 94
“(D) The effect of chemotherapy (Dacarbazine as an example) on enhanced T-cell trafficking to the tumor, including the increased chemokine CCL5, CXCL9, and CXCL10 secretion by tumor cells and macrophages.”
BackgroundInfluentialToward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop
Society for Immunotherapy of Cancer (SITC) Cancer Immune Responsiveness Task Force and Working Groups, Bedognetti, D., Ceccarelli, M., Galluzzi, L., Lu, R. O., Palucka, K., Samayoa, J. A., Spranger, S., Warren, S. E., Wong, K., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0602-4 · Cited by 90
Drug repurposing to overcome resistance to various therapies for colorectal cancer
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NLRC4 suppresses melanoma tumor progression independently of inflammasome activation
Janowski, A. M., Colegio, O. R., Hornick, E. E., McNiff, J. M., Martin, M. D., Badovinac, V. P., Norian, L. A., Zhang, W., Cassel, S. L., & Sutterwala, F. S. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86953 · Cited by 94
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“Nonetheless, other chemoattractants such as CXCL9, CXCL11, CCL5, and SDF-1 can also promote T trafficking in tumors (8, 9, 14, 21, 43).”
BackgroundTargeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers
Jacquelot, N., Duong, C. P. M., Belz, G. T., & Zitvogel, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02480 · Cited by 89
“found that a restricted signature of six chemokines, CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, were preferentially expressed in melanoma metastases that were highly infiltrated by T cells (87).”
BackgroundDoron, H., Amer, M., Ershaid, N., Blazquez, R., Shani, O., Lahav, T. G., Cohen, N., Adler, O., Hakim, Z., Pozzi, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.033 · Cited by 87
“Since melanoma cells also express CXCL10 (Harlin et al., 2009; Mauldin et al., 2015), we wanted to specifically analyze the functional importance of astrocyte-derived CXCL10 for melanoma cell migration.”
BackgroundAdvancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment
Titov, A., Valiullina, A., Zmievskaya, E., Zaikova, E. K., Petukhov, A., Рифкатовна, М. Р., Bulatov, E., & Rizvanov, A. A. (2020) · Cancers · doi:10.3390/cancers12010125 · Cited by 89
Recent Update of HDAC Inhibitors in Lymphoma
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“Thus, targeting CD8 + t cell could be a solution to reduction of tumor immunity (Dong and Chen, 2003; Harlin et al., 2009; Spranger et al., 2013).”
BackgroundChimeric Antigen Receptor (CAR) T Cell Therapy for Metastatic Melanoma: Challenges and Road Ahead
Soltantoyeh, T., Akbari, B., Karimi, A., Chalbatani, G. M., Ghahri-Saremi, N., Hadjati, J., Hamblin, M. R., & Mirzaei, H. R. (2021) · Cells · doi:10.3390/cells10061450 · Cited by 89
“A study looking at metastatic melanoma biopsies showed that up-regulation of several chemokines, including CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10 could be correlated with the presence of T cells in the tumor [210].”
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“a Oncomine studies showing AKAP12 downregulation in metastases of sarcoma, melanoma, and breast cancer compared to primary-site tumors [81–83] (cancergenome.”
Tumor and Host Factors Controlling Antitumor Immunity and Efficacy of Cancer Immunotherapy
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Restoring tumor immunogenicity with dendritic cell reprogramming
Zimmermannová, O., Ferreira, A. G., Ascic, E., Santiago, M. V., Kurochkin, I., Hansen, M., Met, Ö., Caiado, I., Shapiro, I. E., Michaux, J., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.add4817 · Cited by 89
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Jin, P., Zhao, Y., Liu, H., Chen, J., Ren, J., Jin, J., Bedognetti, D., Liu, S., Wang, E., Marincola, F. M., et al. (2016) · Scientific Reports · doi:10.1038/srep26345 · Cited by 84
Immune checkpoint modulation: Rational design of combination strategies
Zamarin, D., & Postow, M. A. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.01.003 · Cited by 85
Giannini, R., Moretti, S., Ugolini, C., Macerola, E., Menicali, E., Nucci, N., Morelli, S., Colella, R., Mandarano, M., Sidoni, A., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01167 · Cited by 85
Materials for Improving Immune Cell Transfection
Kumar, A. R. K., Shou, Y., Chan, B., Krishaa, L., & Tay, A. K. P. (2021) · Advanced Materials · doi:10.1002/adma.202007421 · Cited by 83
Mihm, M. C., & Mulé, J. J. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0143 · Cited by 83
“Harlin and colleagues (55) suggested that a lack of critical chemokines in a subset of melanoma metastases might limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.”
BackgroundSeo, W., Shimizu, K., Kojo, S., Okeke, A., Kohwi-shigematsu, T., Fujii, S., & Taniuchi, I. (2020) · Nature Communications · doi:10.1038/s41467-020-15375-w · Cited by 85
Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy
Hailemichael, Y., Woods, A. N., Fu, T., He, Q., Nielsen, M. C., Hasan, F., Roszik, J., Xiao, Z., Vianden, C., Khong, H., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci93303 · Cited by 81
“The presence of immune cells in human melanomas correlated with the expression of defined chemokine subsets (29, 68).”
BackgroundStromal Modulation Reverses Primary Resistance to Immune Checkpoint Blockade in Pancreatic Cancer
Zhao, J., Xiao, Z., Li, T., Chen, H., Yuan, Y., Wang, Y., Hsiao, C.-H., Chow, D. S., Overwijk, W. W., & Li, C. (2018) · ACS Nano · doi:10.1021/acsnano.8b02481 · Cited by 81
KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2–CXCL10 Axis in Colorectal Cancer
Liang, W., Liu, H., Zeng, Z., Liang, Z., Xie, H., Li, W., Xiong, L., Liu, Z., Chen, M., Jie, H., et al. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-22-0814 · Cited by 82
“Rapidly accumulating data have begun to elucidate that tumors inhibit T-lymphocyte in fi ltration through multiple pathways, including immunoediting of tumor neoantigens (7), modi fi ed chemokine expressionpro fi les(8),hijackingoftheT-cellcheckpointpathways(9), and abnormal vasculature (10).”
Indicators of responsiveness to immune checkpoint inhibitors
Shields, B. D., Mahmoud, F. A., Taylor, E. M., Byrum, S. D., Sengupta, D., Koss, B. S., Baldini, G., Ransom, S. C., Cline, K., Mackintosh, S. G., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01000-2 · Cited by 81
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“Moreover, CCL3, CCL4, and CCL5 are preferentially expressed in tumors with T-cell infiltration in melanoma patients (47).”
BackgroundCAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success
Long, K. B., Young, R. M., Boesteanu, A. C., Suhoski, M. M., Melenhorst, J. J., Lacey, S. F., Degaramo, D. A., Levine, B. L., & Fraietta, J. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02740 · Cited by 80
“For example, melanoma cells do not produce sufficient amounts of CXCR3 ligands and this results in inefficient localization of CXCR3 receptor-bearing effector CD8 T cells to metastatic sites (57).”
BackgroundTumor microenvironment and lymphocyte infiltration
Rahir, G., & Moser, M. (2012) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-012-1253-1 · Cited by 81
Weiss, G. R., Grosh, W. W., Chianese‐Bullock, K. A., Zhao, Y., Liu, H., Slingluff, C. L., Marincola, F. M., & Wang, E. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1650 · Cited by 78
“Experimental animal models provide a mechanistic interpretation of these findings, suggesting a role for IFN-dependent chemokine release guiding the homing of effector immune cells to the tumor site (39, 40).”
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Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update
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“In a subset of patients with melanoma metastases, lack of chemoattractants coincides with limited migration of CD8 T cells and limited presence of lymphoid structures (154).”
BackgroundChemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma
Jacquelot, N., Enot, D. P., Flament, C., Vimond, N., Blattner, C., Pitt, J. M., Yamazaki, T., Roberti, M. P., Daillère, R., Vétizou, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci80071 · Cited by 79
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“Contrary to the “pro-inflammatory” chemokines, found in a subset of patients with pre-existing TIL infiltration,(18) chemokines responsible for tumor progression through induction of angiogenesis, metastasis and recruitment of immune suppressive cell subsets such as CXCL8/IL8, CXCL12/SDF-1 and CCL22 are widely express…”
BackgroundInfluentialUncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle
Cheng, W.-C., Tsui, Y., Ragusa, S., Koelzer, V. H., Mina, M., Franco, F., Laubli, H. P., Tschumi, B., Speiser, D. E., Romero, P. J., et al. (2019) · Nature Immunology · doi:10.1038/s41590-018-0290-0 · Cited by 77
Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity
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Leibowitz, M. S., Srivastava, R. M., Filho, P. A. A., Egloff, A. M., Wang, L., Seethala, R. R., Ferrone, S., & Ferris, R. L. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1517 · Cited by 76
“Indeed, successful T-cell–based immunotherapy has been linked to CXCR3 expression as a biomarker for active, tumor homing TH1 antitumor lymphocytes (35, 48).”
Background
Metadata
- Authors
- Harlin, H., Meng, Y., Peterson, A. C., Zha, Y., Tretiakova, M., Slingluff, C., McKee, M., & Gajewski, T. F.
- Affiliations
- 1Department of Pathology,
- 2Department of Medicine, Section of Hematology/Oncology, and
- University of Virginia (US)
- University of Chicago (US)
- Venue
- Cancer Research
- Published
- 2009-04-01
- Volume
- 69
- Issue
- 7
- Pages
- 3077-3085
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3886718
- OpenAlex
- W2162222767
- Cited by
- 1,121
- References
- 29
- Citations by year
- 2026: 40 · 2025: 58 · 2024: 89 · 2023: 95 · 2022: 118 · 2021: 121 · 2020: 105 · 2019: 87 · 2018: 69 · 2017: 77 · 2016: 51 · 2015: 42 · 2014: 29 · 2013: 37 · 2012: 28
- FWCI
- 17.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Burroughs Wellcome Fund
- University of Chicago
- National Cancer Institute (P01CA97296, R01 CA90575, R01CA090575, P01CA097296, P30CA044579)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- melanoma metastasis, chemokines, CD8+ T cell recruitment, T cell migration, MCP-1, CCL3, carbon tetrachloride, RANTES, CXCL9, CXCL10, chemokine receptors, tumor immune microenvironment, chemokine blockade, antitumor immunity, melanoma cell lines, xenografts
- MeSH terms
- Cell Movement, Multigene Family, Humans, Melanoma, Gene Expression, CD8-Positive T-Lymphocytes, Chemokines, Protein Array Analysis, Cell Line, Tumor
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