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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]
In the citing paper
“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
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
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
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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).”
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
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).”
BackgroundUyttenhove, 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).”
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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Items 701–800 of 1,001
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“Subsequently, pembrolizumab and nivolumab were approved in 2014 and were shown to improve overall survival in patients with metastatic melanoma compared with that achieved with ipilimumab or chemotherapy [100–105].”
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Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure
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“Similar to PD-L1, indoleamine 2,3-dioxygenase (IDO) expression can also be influenced by IFN-γ, and can lead to primary resistance to PD-1 blockade [38].”
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“This is consistent with depletion of CD8 T-cells or IFNγ-deficiency diminishing IDO1 expression in tumor stroma in murine melanoma.(36) IFNγ-induced expression of IDO1 in endothelial cells has previously been observed in a model of allotransplantation, where CD40Ig-induced graft acceptance of a complete MHC-mismatched…”
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Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma
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Biological Factors behind Melanoma Response to Immune Checkpoint Inhibitors
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Therapeutic vaccination strategies to treat nasopharyngeal carcinoma
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“This result is not entirely unexpected, as we failed to find substantial PD-L1 expression on tumor cells at any time point, a predictor of response to anti-PD-1 blockade [40].”
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Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC
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“In support of this, treatment success in melanoma and other cancers with inherently high mutational load has been attributed to a “T cell inflamed” or “hot” tumor microenvironment (TME), associated with enhanced infiltration of CD8 T cells along with B cells, macrophages, FOXP3 cells, and type I and II IFN signatures.…”
BackgroundBreakthrough concepts in immune-oncology: Cancer vaccines at the bedside
Roy, S., Sethi, T. K., Taylor, D., Kim, Y. J., & Johnson, D. B. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.5bt0420-585rr · Cited by 44
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“Improved survival to MIBC depended on IFNg production after immunotherapy, as already described formelanoma (66) ormetastatic bladder cancer (44).”
BackgroundAdvancements in Cancer Immunotherapies
Roy, R., Singh, S. K., & Misra, S. (2022) · Vaccines · doi:10.3390/vaccines11010059 · Cited by 44
“PD-L1 Atezolizumab (Tecentriq) Bladder, NSCLC (2016), and TNBC (2019), hepatocellular carcinoma, HCC (2020) FDA approved [69] [74,75] Avelumab (Bavencio) Urothelial Carcinoma (2017), Merkel Cell Carcinoma (2017), Renal carcinoma (2019) FDA approved [74] MED14736 Multiple cancers Phase III [69] Avelumab (Bavencio) Merk…”
BackgroundTargeting the Innate Immune System as Immunotherapy for Acute Myeloid Leukemia
Curran, E. K., Corrales, L. P., & Kline, J. P. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00083 · Cited by 41
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Galectins as pivotal components in oncogenesis and immune exclusion in human malignancies
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“This could be explained if we take into consideration that both Gal-9 and PD-L1 are upregulated following IFNg signaling (111, 112), possibly reflecting strong ongoing immunoreactivity, backed by the strong TIL infiltration.”
BackgroundThe catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1
Panfili, E., Mondanelli, G., Orabona, C., Gargaro, M., Volpi, C., Belladonna, M. L., Rossini, S., Suvieri, C., & Pallotta, M. T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1134551 · Cited by 40
The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment
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Mutation Drivers of Immunological Responses to Cancer
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Cellular Phenotype Plasticity in Cancer Dormancy and Metastasis
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Toward T Cell-Mediated Control or Elimination of HIV Reservoirs: Lessons From Cancer Immunology
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“suppression of adaptive immune responses (75).”
BackgroundLiao, H., Chen, W., Dai, Y., Richardson, J. J., Guo, J., Yuan, K., Zeng, Y., & Xie, K. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00883 · Cited by 41
Shi, J., Chen, C., Jü, R., Wang, Q., Li, J., Guo, L., Ye, C., & Zhang, D. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0725-7 · Cited by 40
Pinard, C., Debled, M., Rejeb, H. B., Velasco, V., de Lara, C. T., Hoppe, S., Richard, É., Brouste, V., Bonnefoi, H. R., & MacGrogan, G. M. (2019) · Breast Cancer Research and Treatment · doi:10.1007/s10549-019-05437-z · Cited by 40
Cancer Nano-Immunotherapy from the Injection to the Target: The Role of Protein Corona
Mikelez-Alonso, I., Aires, A., & Cortajarena, A. L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020519 · Cited by 41
The tumour immune landscape and its implications in cutaneous melanoma
Attrill, G. H., Ferguson, P. M., Palendira, U., Long, G. V., Wilmott, J. S., & Scolyer, R. A. (2020) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12926 · Cited by 40
“Conversely, high Treg populations have also been associated with a high number of CD8+ T cells, and yet other studies find that Tregs do not significantly impact survival (Spranger et al., 2013; Weiss et al., 2016).”
ResultTuran, T., Kongpachith, S., Halliwill, K. D., Roelands, J. P., Hendrickx, W., Marincola, F. M., Hudson, T. J., Jacob, H. J., Bedognetti, D., Samayoa, J. A., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01145-4 · Cited by 40
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“The marginal IDO effect was proposed to be indicative of an effective IFNγ antitumor T cell response inducing, among others, immunomodulatory factors like PD-L1 and IDO expression in tumor cells (39, 52).”
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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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