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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CD8+IFN-γ+ T cells are an effector population shown to be a target of downstream STING signaling involving the IFN-β-CXCL9/10 axis.
“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]
The Results section (page unavailable) shows that CXCL9 and CXCL10 recruit human CD8+ effector T cells in migration assays. It does not identify those cells as IFN-γ+ or establish that their recruitment is downstream of STING signaling through IFN-β. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTumors in patients who have sustained responses to checkpoint inhibitors mostly show a T cell-inflamed microenvironment before or early in treatment.
“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]
Metastatic melanoma patients receiving vaccine and cytokine therapies show two broad tumor phenotypes: T cell-inflamed and non-T cell-inflamed.
“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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- 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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