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Up-Regulation of PD-L1, IDO, and T regs in the Melanoma Tumor Microenvironment Is Driven by CD8 + T Cells
Open accessAbstract
Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8(+) T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T(regs), in the tumor microenvironment depended on the presence of CD8(+) T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell-inflamed tumor microenvironment.
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“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 [7]
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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 [7]
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1 retracted
FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer
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“Previous work has shown that antigen-presenting cells in the tumor microenvironment can be tolerogenic (37), and that some cytokines abundant in the tumor, such as IL-10, can inhibit dendritic cell activation and result in T cell anergy (38).”
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“…has been observed in the case of interleukin-2 (IL-2) for melanoma and kidney cancer (1), experimental cancer vaccines (2), and the recently U.S. Food and Drug Administration–approved agents Provenge for prostate cancer (3) and anti– CTLA-4 monoclonal antibody (mAb) (ipilimumab) for melanoma (4).”
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“IDO is a tryptophanmetabolizing enzyme that has been shown to contribute to peripheral immunologic tolerance (25).”
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“…in mouse models include extrinsic suppression of CD8 + effector cells by CD4 + CD25 + FoxP3 + regulatory T cells (T regs ) (6), metabolic deregulation via tryptophan catabolism by indoleamine-2,3-dioxygenase (IDO) (7), and engagement of the inhibitory receptor PD-1 by the ligand PD-L1/B7-H1 (8, 9).”
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BackgroundLow-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non–Small Cell Lung Cancer
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BackgroundInterferons in cancer immunoediting: sculpting metastasis and immunotherapy response
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“Similar findings were observed when we repeated the experiment with another clone of anti-PD-1 antibody (RMP1-14 clone) (Figure S2C; p < 0.05) or anti-PD-L1 antibody (10F.9G2 clone) (Figure S2D; p < 0.01).”
Influential
Metadata
- Authors
- Spranger, S., Spaapen, R. M., Zha, Y., Williams, J., Meng, Y., Ha, T. T., & Gajewski, T. F.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Spranger, Stefani
- Spaapen, Robbert M.
- Gajewski, Thomas F.
- Venue
- Science Translational Medicine
- Published
- 2013-08-28
- Volume
- 5
- Issue
- 200
- Pages
- 200ra116-200ra116
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4136707
- OpenAlex
- W2136731993
- Cited by
- 1,677
- References
- 50
- Citations by year
- 2026: 49 · 2025: 76 · 2024: 112 · 2023: 122 · 2022: 136 · 2021: 173 · 2020: 158 · 2019: 162 · 2018: 171 · 2017: 176 · 2016: 155 · 2015: 111 · 2014: 70 · 2013: 6
- FWCI
- 61.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA127475, R01CA118153)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- melanoma, tumor microenvironment, PD-L1, indoleamine 2,3-dioxygenase, regulatory T cells, CD8+ T cells, immunosuppression, immune checkpoint, interferon-gamma, cancer immunotherapy, tumor immune evasion
- MeSH terms
- Animals, Humans, Interferon-gamma, Lymphocyte Activation, Melanoma, Melanoma, Experimental, Neoplasm Metastasis, Up-Regulation, CD8-Positive T-Lymphocytes, Chemokines, Xenograft Model Antitumor Assays, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Tumor Microenvironment, B7-H1 Antigen
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