Cited by 1,677Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Up-Regulation of PD-L1, IDO, and T regs in the Melanoma Tumor Microenvironment Is Driven by CD8 + T Cells

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Spranger, Stefani, Spaapen, Robbert M., Zha, Yuanyuan, Williams, Jason, Meng, Yuru, Ha, Thanh T., Gajewski, Thomas F.·2013·Science Translational Medicine

DOI 10.1126/scitranslmed.3006504PMC PMC4136707

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Abstract

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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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).”
Background
Retracted
Improved 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).”
Background
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
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Sipuleucel-T Immunotherapy for Castration-Resistant Prostate 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).”
Background
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
Curiel, 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).”
Background
Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates
Brahmer, 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).”
Background
Prevention of Allogeneic Fetal Rejection by Tryptophan Catabolism
Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I. E., Conway, S. J., Marshall, B., Brown, C. C., & Mellor, A. L. (1998) · Science · doi:10.1126/science.281.5380.1191 · Cited by 2,589 · cited 1×
“IDO is a tryptophanmetabolizing enzyme that has been shown to contribute to peripheral immunologic tolerance (25).”
Background
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase
Uyttenhove, C., Pilotte, L., Théate, I., Stroobant, V., Colau, D., Parmentier, N., Boon, T., & Van den Eynde, B. J. (2003) · Nature Medicine · doi:10.1038/nm934 · Cited by 2,305 · cited 1×
“…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).”
Background
Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape
Taube, 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).”
Background

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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.
ORCID: Spranger, Stefani
Spaapen, Robbert M.
Zha, Yuanyuan
Williams, Jason
Gajewski, Thomas F.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2013-08-28
Volume: 5
Issue: 200
Pages: 200ra116-200ra116
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.3006504
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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Up-Regulation of PD-L1, IDO, and T regs in the Melanoma Tumor Microenvironment Is Driven by CD8 + T Cells

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