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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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“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]
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 [7]
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1 retracted
FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer
Watkins, S. K., Zhu, Z., Riboldi, E., Shafer-Weaver, K., Stagliano, K. E., Sklavos, M. M., Ambs, S., Yagita∥, H., & Hurwitz, A. A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44325 · Cited by 137 · cited 1×
“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).”
BackgroundRetractedImproved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155 · cited 1×
“…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).”
BackgroundSafety, activity, and immune correlates of anti–PD-1 antibody in cancer
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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).”
BackgroundCuriel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., et al. (2004) · Nature Medicine · doi:10.1038/nm1093 · Cited by 5,151 · cited 1×
“Although direct CCL22 production by tumor cells in other cancer types also has been suggested (34), we did not detect CCL22 mRNA expression in a series of melanoma cell lines, arguing that in the melanoma context, it is likely derived from infiltrating nontumor stromal cells (13).”
BackgroundBrahmer, J. R., Drake, C. G., WOLLNER, I. S., Powderly, J. D., Picus, J., Sharfman, W. H., Stankevich, E., Pons, A., Salay, T. M., McMiller, T. L., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.7609 · Cited by 2,967 · cited 1×
“Clinical strategies to counter these immunosuppressive pathways are currently being evaluated, already with encouraging early-phase clinical trial results (10–12).”
BackgroundPrevention of Allogeneic Fetal Rejection by Tryptophan Catabolism
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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).”
BackgroundTaube, J. M., Anders, R. A., Young, G. D., Xu, H., Sharma, R., McMiller, T. L., Chen, S., Klein, A. P., Pardoll, D. M., Topalian, S. L., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003689 · Cited by 2,157 · cited 2×
“It has been speculated that clinical response to antibodies targeting the PD-L1/PD-1 interaction may end up being restricted to cases in which PD-L1 expression is associated with a CD8 + T cell infiltrate and therefore is likely blunting host immunity (32).”
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“…(13, 14), mounting evidence indicates that chronically elevated IFN-I signaling can lead to T cell dysfunction and exhaustion by inducing the expression of negative regulators (15–17) as well as attrition of activated T cells (18) during chronic infections and in the tumor microenvironment.”
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“DAMPs increase IFN-γ production, which upregulates PD-L1 expression in cytotoxic CD8+ T cells, and recruit regulatory T cells via CCR4-binding chemokines [19].”
BackgroundImmunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function
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“In addition, the tumor microenvironment (TME) itself can suppress T-cell function through oxygen depletion (hypoxia), nutrient deprivation, and production of immunosuppressive metabolites, including lactic acid and adenosine (1, 2).”
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Cancer immunology – development of novel anti-cancer therapies
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“The adaptive CD8+ T cells, CAFs, M2-like macrophages, and corresponding cytokines were revealed to engage in the dynamic change of PD-L1 within local tumors (106,108,111).”
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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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