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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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InfluentialErdag, G., Schaefer, J. T., Smolkin, M. E., Deacon, D. H., Shea, S. M., Dengel, L. T., Patterson, J. W., & Slingluff, C. L. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3218 · Cited by 610
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“The clinical relevance of these immune and cancer cell factors is highlighted by common biomarkers for ICB response such as type I or II interferon (IFN) stimulated genes (ISGs) (Ayers et al., 2017; Harlin et al., 2009), tumor mutational burden (TMB) (Rizvi et al.”
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“Moreover, CXCR3 expression by peripheral CD8+ T cells is associated with survival (48), whereas expression of the corresponding chemokines — CXCL9 and CXCL10 — by metastases is associated with CD8+ T cell recruitment (49).”
BackgroundDirect Effects of Type I Interferons on Cells of the Immune System
Hervás‐Stubbs, S., Perez‐Gracia, J. L., Rouzaut, A., Sanmamed, M. F., Bon, A. L., & Melero, I. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1114 · Cited by 535
The Next Hurdle in Cancer Immunotherapy: Overcoming the Non–T-Cell–Inflamed Tumor Microenvironment
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“A second approach for promoting innate immune activation directly within the tumor microenvironment has been to provide an increased local concentration of type I IFNs.”
BackgroundMethodInfluentialThe host STING pathway at the interface of cancer and immunity
Corrales, L., McWhirter, S. M., Dubensky, T. W., & Gajewski, T. F. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86892 · Cited by 487
“Within the tumor microenvironment, T cells, endothelial cells, and fibroblasts all have been observed to produce type I IFNs upon stimulation with STING agonists ex vivo; however, the magnitude of type I IFN production was substantially lower compared with macrophages and DCs (8).”
BackgroundInfluentialSelf-citationAdoptive T Cell Transfer for Cancer Immunotherapy in the Era of Synthetic Biology
Kalos, M. D., & June, C. H. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.002 · Cited by 501
“Critical and significant challenges remain with regard to understanding the mechanisms and obstacles that impact effective T cell infiltration of solid tumors (Fisher et al., 2006; Harlin et al., 2009).”
Beyond immune checkpoint blockade: emerging immunological strategies
Kubli, S. P., Berger, T., Araújo, D. V., Siu, L. L., & Mak, T. W. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00155-y · Cited by 465
Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma
Gide, T. N., Wilmott, J. S., Scolyer, R. A., & Long, G. V. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2267 · Cited by 469
STING: a master regulator in the cancer-immunity cycle
Zhu, Y., An, X., Zhang, X., Qiao, Y., Zheng, T., & Li, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1087-y · Cited by 431
Resistance Mechanisms to Anti-PD Cancer Immunotherapy
Vesely, M. D., Zhang, T., & Chen, L. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-070621-030155 · Cited by 468
Bos, R., & Sherman, L. A. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1322 · Cited by 445
“Others have also shown the importance of an IFN-γ dependent increase in the expression of Th1 chemokines within the tumor environment (9) and these chemokines have been described to be preferentially expressed in human tumors that contain T cells (32).”
BackgroundMelero, I., Rouzaut, A., Motz, G. T., & Coukos, G. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0985 · Cited by 452
“Among the cytokines that best induce chemoattractants, the IL-12–IFN-γ–CXCL10/11 axis stands out, together with type I IFN-α and IFN-β.”
InfluentialPredictive Gene Signature in MAGE-A3 Antigen-Specific Cancer Immunotherapy
Ulloa-Montoya, F., Louahed, J., Dizier, B., Gruselle, O., Spiessens, B., Lehmann, F. F., Suciu, S., Kruit, W. H. J., Eggermont, A. M. M., Vansteenkiste, J., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.3762 · Cited by 436
Coppola, D., Nebozhyn, M., Khalil, F., Dai, H., Yeatman, T., Loboda, A., & Mulé, J. J. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.03.007 · Cited by 434
Interferons α and β in cancer: therapeutic opportunities from new insights
Borden, E. C. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0011-2 · Cited by 428
Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment
Gajewski, T. F., Woo, S., Zha, Y., Spaapen, R. M., Zheng, Y., Corrales, L. P., & Spranger, S. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.02.009 · Cited by 429
Labadie, B. W., Bao, R., & Luke, J. J. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2882 · Cited by 413
“A contrarian view to acknowledge surrounding this pathway would be that in a T cellinflamed tumor, inhibition of Trp-Kyn-AhR may be insufficient to elicit further antitumor immune response due to the presence of further escape mechanisms (6,7,15).”
BackgroundInfluentialTrafficking of T Cells into Tumors
Slaney, C. Y., Kershaw, M. H., & Darcy, P. K. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-2458 · Cited by 413
Innate immune signaling and regulation in cancer immunotherapy
Corrales, L., Matson, V., Flood, B., Spranger, S., & Gajewski, T. F. (2017) · Cell Research · doi:10.1038/cr.2016.149 · Cited by 408
Self-citationSpranger, S., Luke, J. J., Bao, R., Zha, Y., Hernandez, K. M., Yan, L., Gajewski, A. P., Andrade, J., & Gajewski, T. F. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609376113 · Cited by 403
“In fact, we and others have observed a highly significant correlation between the degree of T-cell infiltration and the predominantly tumor cell-derived expression of CCL3, CCL4, and CCL5, all chemokines binding to the CCR5 receptor, suggesting a potentially strong correlation between chemokine suppression, lack of DC…”
BackgroundResultInfluentialFates of CD8+ T cells in Tumor Microenvironment
Maimela, N. R., Liu, S., & Zhang, Y. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2018.11.004 · Cited by 459
The chemokine system in cancer biology and therapy
Mantovani, A., Savino, B., Locati, M., Zammataro, L. A., Allavena, P., & Bonecchi, R. (2009) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.11.007 · Cited by 407
“Consistently with this, in mouse tumor models [49] and in human biopsies of breast carcinoma [50,51], melanoma [52], esophageal carcinoma [53], colon cancer [54], prostate carcinoma”
BackgroundTrujillo, J., Sweis, R. F., Bao, R., & Luke, J. J. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0277 · Cited by 396
“Gene expression profiling of baseline biopsies of melanoma metastases has revealed two major subsets of tumors characterized by high (T cell–inflamed) or low (non-T cell–inflamed) expression of genes indicative of a preexisting T-cell infiltrate (12, 13).”
BackgroundTargeting CCL5 in inflammation
Marques, R. E., Guabiraba, R., Russo, R. C., & Teixeira, M. M. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.837886 · Cited by 384
“CCL5 is expressed in a variety of cancer and metastatic processes, such as breast carcinoma [127], melanoma [128] and papillary thyroid carcinoma [129].”
BackgroundLim, S. Y., Lee, J. H., Gide, T. N., Menzies, A. M., Guminski, A., Carlino, M. S., Breen, E. J., Yang, J. Y. H., Ghazanfar, S., Kefford, R. F., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2795 · Cited by 381
“18 19 Cytokines are important regulators of host immune activity; they promote the recruitment of 20 immune cells into the tumor microenvironment (13-17), and induce the expression of 21 immune checkpoint inhibitors, including TIM-3 and PD-1 (18).”
BackgroundChemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy
Vilgelm, A. E., & Richmond, A. J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00333 · Cited by 378
“For example, in melanoma, the lack of CCR5 ligands (CCL3, CCL4, CCL5) and CXCR3 ligands (CXCL9 and CXCL10) has been associated with limited infiltration of antigen-specific T cells (103).”
BackgroundNociceptor neurons affect cancer immunosurveillance
Balood, M., Ahmadi, M., Eichwald, T., Ahmadi, A., Majdoubi, A., Roversi, K., Roversi, K., Lucido, C. T., Restaino, A. C., Huang, S., et al. (2022) · Nature · doi:10.1038/s41586-022-05374-w · Cited by 405
Immunologic tumor microenvironment modulators for turning cold tumors hot
Khosravi, G. R., Mostafavi, S., Bastan, S., Ebrahimi, N., Gharibvand, R. S., & Eskandari, N. (2024) · 癌症：英文版 · doi:10.1002/cac2.12539 · Cited by 403
“However, tumors significantly deregulate cytokine and chemokine secretion, as chemokines participating in T lymphocyte recruitment are dramatically decreased in non-CD8 + T cell-inflamed tumors [74].”
BackgroundType I interferon response and innate immune sensing of cancer
Fuertes, M. B., Woo, S.-R., Burnett, B., Fu, Y.-X., & Gajewski, T. F. (2013) · Trends in Immunology · doi:10.1016/j.it.2012.10.004 · Cited by 375
“Gene expression profiling done on human metastatic melanoma biopsies revealed the existence of a subset of samples with an inflamed phenotype which contained activated CD8+ T cells [42], that include tumor-reactive cells [43].”
Mechanisms regulating T-cell infiltration and activity in solid tumors
Lanitis, E., Dangaj, D., Irving, M., & Coukos, G. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx238 · Cited by 369
“Alternatively, tumors such as ovarian can use epigenetic mechan- isms to silence the T-cell attracting chemokines CXCL9 and CXCL10 [97].”
BackgroundInfluentialChemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy
Garland, K. M., Sheehy, T. L., & Wilson, J. T. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00750 · Cited by 372
Molecular Drivers of the Non–T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer
Sweis, R. F., Spranger, S., Bao, R., Paner, G. P., Stadler, W. M., Steinberg, G. D., & Gajewski, T. F. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0274 · Cited by 356
“The immunohistochemical staining (IHC) on human bladder tumors was performed by the Human Tissue Resource Center (HTRC) at the University of Chicago using tissue from cystectomy specimens from muscle-invasive bladder cancer, corresponding to specimens previously submitted for inclusion in the TCGA.”
BackgroundMethodInfluentialMajor pathways involved in macrophage polarization in cancer
Kerneur, C., Cano, C. E., & Olive, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1026954 · Cited by 363
“These cells are also able to activate CD8+ cytotoxic T cells (35), which are the most potent anticancer immune effectors and constitute the foundation of current effective cancer immunotherapies (36) through the secretion of the chemokines previously listed (CCL2, CCL3, CCL4, CCL5 and CXCL10) (37).”
BackgroundInfluentialSTING pathway agonism as a cancer therapeutic
Flood, B. A., Higgs, E. F., Li, S., Luke, J. J., & Gajewski, T. F. (2019) · Immunological Reviews · doi:10.1111/imr.12765 · Cited by 340
Designing Vaccines Based on Biology of Human Dendritic Cell Subsets
Palucka, K., Banchereau, J., & Mellman, I. (2010) · Immunity · doi:10.1016/j.immuni.2010.10.007 · Cited by 341
Srivastava, S., Furlan, S. N., Jaeger-Ruckstuhl, C. A., Sarvothama, M., Berger, C., Smythe, K. S., Garrison, S. M., Specht, J. M., Lee, S. M., Amezquita, R. A., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.11.005 · Cited by 327
Migrating into the tumor: a roadmap for T cells
van der Woude, L. L., Gorris, M. A. J., Halilovic, A., Figdor, C. G., & de Vries, I. J. M. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.09.006 · Cited by 307
WNT/β-Catenin Signaling Pathway Regulating T Cell-Inflammation in the Tumor Microenvironment
Li, X., Xiang, Y., Li, F., Yin, C., Li, B., & Ke, X. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02293 · Cited by 291
“The expression of chemokines C-C motif chemokine ligand (CCL) 2, CCL3, CCL4, CCL5, C-X-C motif chemokine ligand (CXCL) 9, and CXCL10 is associated with the infiltration of T cells, and each of these chemokines is sufficient to recruit CD8 effector T cells in vitro (16).”
BackgroundResultPaulson, K. G., Iyer, J. G., Tegeder, A. R., Thibodeau, R. M., Schelter, J. M., Koba, S., Schrama, D., Simonson, W. T., Lemos, B. D., Byrd, D. R., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.6308 · Cited by 303
Halama, N., Braun, M., Kahlert, C., Spille, A., Breunig, C., Rahbari, N. N., Koch, M., Weitz, J., Kloor, M., Zoernig, I., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2173 · Cited by 300
Spranger, S. (2016) · International Immunology · doi:10.1093/intimm/dxw014 · Cited by 300
How chemokines organize the tumour microenvironment
Mempel, T. R., Lill, J. K., & Altenburger, L. M. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00635-w · Cited by 317
“…a correlation between T cell infiltration of human melanoma with the expression of these chemokines, along with other type 1 immunity chemokines 38 , and CXCR3 was found to be necessary for intratumoural accumulation of CD8 + T cells 39 and of adoptively transferred CD27 hi NK cells in mouse…”
Petty, A. J., Li, A., Wang, X., Dai, R., Heyman, B. M., Hsu, D. S., Huang, X., & Yang, Y. (2019) · Journal of Clinical Investigation · doi:10.1172/jci128644 · Cited by 297
“Additionally, elevated levels of CXCL9 and CXCL10 are positively correlated with intratumoral T cell infiltration and thus better prognosis in melanoma, serous ovarian cancer, and colorectal cancer patients (41, 42).”
BackgroundJönsson, G. B., Busch, C., Knappskog, S., Geisler, J., Miletić, H., Ringnér, M., Lillehaug, J. R., Borg, Å., & Lønning, P. E. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2509 · Cited by 285
“Others have identified critical chemokines to be crucial for the recruitment of CD8 T-cells in melanoma (35).”
Gajewski, T. F., Corrales, L. P., Williams, J. B., Horton, B. L., Sivan, A., & Spranger, S. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-67577-0_2 · Cited by 284
“A major clue came from the observation that tumors that contained a T cell infiltrate also showed evidence for a transcriptional signature known to be induced by type I IFNs [3, 36].”
BackgroundInfluentialCXCR3 Ligands in Cancer and Autoimmunity, Chemoattraction of Effector T Cells, and Beyond
Karin, N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00976 · Cited by 285
Butterfield, L. H. (2015) · BMJ · doi:10.1136/bmj.h988 · Cited by 288
Cancer immune evasion, immunoediting and intratumour heterogeneity
Roerden, M., & Spranger, S. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-024-01111-8 · Cited by 297
The STING pathway and the T cell-inflamed tumor microenvironment
Woo, S., Corrales, L. P., & Gajewski, T. F. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.003 · Cited by 275
“Melanoma metastases containing evidence for T cell infiltration also showed expression of a type I IFN gene signature [18,44].”
BackgroundInfluential
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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