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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
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
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945
Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer
Kantoff, P. W., Higano, C. S., Shore, N. D., Berger, E. R., Small, E. J., Penson, D. F., Redfern, C. H., Ferrari, A. C., Dreicer, R., Sims, R. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1001294 · Cited by 5,572 · 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).”
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).”
BackgroundCurran, M. A., Montalvo, W., Yagita, H., & Allison, J. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0915174107 · Cited by 1,874 · cited 1×
“Indeed, preclinical data support the notion that combinatorial manipulation of two immunoregulatory pathways can provide synergy for improved immune-mediated tumor control in vivo (6, 45, 46).”
BackgroundA function for interleukin 2 in Foxp3-expressing regulatory T cells
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A., & Rudensky, A. Y. (2005) · Nature Immunology · doi:10.1038/ni1263 · Cited by 1,819 · cited 1×
“The following day, GFP-expressing splenocytes from FoxP3-GFP reporter mice (49) were removed by sorting, and 3 × 10 6 GFP-depleted or total splenocytes were injected intravenously into tumor-bearing mice.”
MethodLoss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma
Parsa, A. T., Waldron, J. S., Panner, A., Crane, C. A., Parney, I. F., Barry, J. J., Cachola, K. E., Murray, J. C., Tihan, T., Jensen, M. C., et al. (2006) · Nature Medicine · doi:10.1038/nm1517 · Cited by 1,341 · cited 1×
“In some tumor cell lines, PD-L1 expression appears to be up-regulated intrinsically via PTEN silencing and Akt activation (31).”
BackgroundFuertes, M. B., Kacha, A. K., Kline, J., Woo, S.-R., Kranz, D. M., Murphy, K. M., & Gajewski, T. F. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20101159 · Cited by 1,192 · cited 2×
“The T cell–inflamed subset also expresses chemokines for T cell recruitment (13) and a type I interferon (IFN) transcriptional profile that appears to participate in innate immune sensing (19, 20).”
BackgroundSelf-citationTumor Rejection After Direct Costimulation of CD8 + T Cells by B7-Transfected Melanoma Cells
Townsend, S. E., & Allison, J. P. (1993) · Science · doi:10.1126/science.7678351 · Cited by 1,139 · cited 1×
“Mechanistic studies have suggested that prevention or reversal of a T cell anergic state can promote tumor rejection in vivo (39–41).”
BackgroundChemokine expression in melanoma metastases associated with CD8+ T-cell recruitment
Harlin, H., Meng, Y., Peterson, A. C., Zha, Y., Tretiakova, M., Slingluff, C., McKee, M., & Gajewski, T. F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2281 · Cited by 1,121 · cited 6×
“The T cell–inflamed subset also expresses chemokines for T cell recruitment (13) and a type I interferon (IFN) transcriptional profile that appears to participate in innate immune sensing (19, 20).”
BackgroundMethodInfluentialCharacterization of circulating T cells specific for tumor-associated antigens in melanoma patients
Lee, P. P., Yee, C., Savage, P. A., Fong, L. H., Brockstedt, D. G., Weber, J. S., Johnson, D. L., Swetter, S. M., Thompson, J. A., Greenberg, P. D., et al. (1999) · Nature Medicine · doi:10.1038/9525 · Cited by 1,117
Type I interferon is selectively required by dendritic cells for immune rejection of tumors
Diamond, M. S., Kinder, M., Matsushita, H., Mashayekhi, M., Dunn, G. P., Archambault, J. M., Lee, H., Arthur, C. D., White, J. M., Kalinke, U., et al. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20101158 · Cited by 1,081 · cited 1×
“The T cell–inflamed subset also expresses chemokines for T cell recruitment (13) and a type I interferon (IFN) transcriptional profile that appears to participate in innate immune sensing (19, 20).”
BackgroundChen, L., Ashe, S., Brady, W. A., Hellström, I., Hellström, K. E., Ledbetter, J. A., McGowan, P., & Linsley, P. S. (1992) · Cell · doi:10.1016/s0092-8674(05)80059-5 · Cited by 1,050
Iellem, A., Mariani, M., Lang, R., Recalde, H. R., Panina‐Bordignon, P., Sinigaglia, F., & D’Ambrosio, D. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.6.847 · Cited by 915 · cited 1×
“Because previous work suggested that chemokines could contribute to T reg accumulation in tissues (28), we evaluated whether CD8 + effector T cells might produce any chemokines capable of T reg recruitment and whether chemokine-mediating trafficking participated in vivo.”
An immune-active tumor microenvironment favors clinical response to ipilimumab
Ji, R., Chasalow, S. D., Wang, L., Hamid, O., Schmidt, H., Cogswell, J. P., Alaparthy, S., Berman, D., Jure‐Kunkel, M., Siemers, N. O., et al. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1172-6 · Cited by 783 · cited 1×
“Clinical responders to melanoma vaccines and to ipilimumab appear to be enriched in the T cell–inflamed subset of tumors, suggesting that an ongoing dialogue between the tumor and the host immune response may be predictive of clinical benefit (14, 21).”
BackgroundBlank, C., Brown, I., Peterson, A. C., Spiotto, M., Iwai, Y., Honjo, T., & Gajewski, T. F. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3259 · Cited by 772 · 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).”
BackgroundErdag, G., Schaefer, J. T., Smolkin, M. E., Deacon, D. H., Shea, S. M., Dengel, L. T., Patterson, J. W., & Slingluff, C. L. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3218 · Cited by 610 · cited 1×
“We and others recently have analyzed a series of melanoma metastases by gene expression profiling and confirmatory assays, and found that some samples contain abundant CD8 + T cell infiltrates and some do not (13–16).”
BackgroundSelective inhibition of IDO1 effectively regulates mediators of antitumor immunity
Liu, X., Shin, N., Koblish, H. K., Yang, G., Wang, Q., Wang, K., Leffet, L., Hansbury, M., Thomas, B. A., Rupar, M. J., et al. (2010) · Blood · doi:10.1182/blood-2009-09-246124 · Cited by 559
Atkins, M. B., Kunkel, L., Sznol, M., & Rosenberg, S. A. (2000) · PubMed · Cited by 515
Steinbrink, K., Jonuleit, H., Müller, G., Schuler, G., Knop, J., & Enk, A. (1999) · Blood · doi:10.1182/blood.v93.5.1634 · Cited by 509
Messina, J. L., Fenstermacher, D. A., Eschrich, S., Qu, X., Berglund, A. E., Lloyd, M. C., Schell, M. J., Sondak, V. K., Weber, J. S., & Mulé, J. J. (2012) · Scientific Reports · doi:10.1038/srep00765 · Cited by 426
PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model
Zhang, L., Gajewski, T. F., & Kline, J. P. (2009) · Blood · doi:10.1182/blood-2009-03-206672 · Cited by 417 · cited 1×
“At day 7, tumors and spleens (as control) were harvested and split in two to be either saved in RNAlater (Ambion Inc.) for RT-PCR analysis or used to prepare single-cell suspensions for immediate FACS analysis for CD4, CD8, PD-L1, and FoxP3 as described (6, 48).”
MethodLee, I. T., Wang, L., Wells, A. D., Dorf, M. E., Özkaynak, E., & Hancock, W. W. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041709 · Cited by 375 · cited 1×
“These results are consistent with reports indicating a role for this chemokine in transplantation tolerance via T reg recruitment (33).”
ResultB7-H1 pathway and its role in the evasion of tumor immunity
Dong, H., & Chen, L. (2003) · Journal of Molecular Medicine · doi:10.1007/s00109-003-0430-2 · Cited by 280 · cited 11×
“Therefore, up-regulated expression of both IDO and PD-L1/B7-H1 in the melanoma tumor microenvironment in vivo depends on CD8 + T cells and IFN-γ .”
BackgroundInfluentialImmune Suppression in the Tumor Microenvironment
Gajewski, T. F., Meng, Y., & Harlin, H. (2006) · Journal of Immunotherapy · doi:10.1097/01.cji.0000199193.29048.56 · Cited by 263 · cited 1×
“Recent work has suggested that one explanation for tumor resistance to immunotherapies might be due to immunosuppressive events that act at the level of the tumor microenvironment (5).”
BackgroundMunn, D. H., & Mellor, A. L. (2003) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2003.11.003 · Cited by 257 · cited 1×
“The fact that IDO and PD-L1 can be induced by proinflammatory cytokines such as IFN-γ in vitro (8, 27) suggested that cytokines produced by activated CD8 + Tcells in the tumor microenvironment could explain the elevated expression of these factors preferentially in inflamed tumors in vivo.”
BackgroundSchwartz, R. H. (1997) · Current Opinion in Immunology · doi:10.1016/s0952-7915(97)80081-7 · Cited by 256
Gajewski, T. F., Louahed, J., & Brichard, V. G. (2010) · The Cancer Journal · doi:10.1097/ppo.0b013e3181eacbd8 · Cited by 250 · cited 3×
“Immune escape in that subset appears to be a consequence of immunologic ignorance and/or immune “exclusion” (13, 14, 30).”
BackgroundSipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer
Tanimoto, T., Hori, A., & Kami, M. (2010) · New England Journal of Medicine · doi:10.1056/nejmc1009982 · Cited by 205
Mortarini, R., Piris, A., Maurichi, A., Molla, A., Bersani, I., Bono, A. V., Bartoli, C., Santinami, M., Lombardo, C., Ravagnani, F., et al. (2003) · PubMed · Cited by 177
Transient T cell depletion causes regression of melanoma metastases
Rasku, M. A., Clem, A. L., Telang, S., Taft, B. S., Gettings, K. F., Gragg, H., Cramer, D. E., Lear, S. C., McMasters, K. M., Miller, D. M., et al. (2008) · Journal of Translational Medicine · doi:10.1186/1479-5876-6-12 · Cited by 158
Peterson, A., Harlin, H., & Gajewski, T. F. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.12.144 · Cited by 154 · cited 2×
“Scienc blood in a subset of patients (2, 17, 18).”
BackgroundAppay, V., Jandus, C., Voelter, V., Reynard, S., Coupland, S. E., Rimoldi, D., Líénard, D., Guillaume, P., Krieg, A. Μ., Cerottini, J., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.3.1670 · Cited by 152
Harlin, H., Kuna, T. V., Peterson, A., Meng, Y., & Gajewski, T. F. (2006) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-005-0118-2 · Cited by 144 · cited 1×
“On the basis of parallel work suggesting dysfunction of CD8 + T cells when analyzed directly from the tumor microenvironment ex vivo (22–24), those tumors were also interrogated for the presence of putative negative regulatory mechanisms that might inhibit effector T cell function.”
BackgroundHoelzinger, D. B., Smith, S. E., Mirza, N. N., Dominguez, A. L., Manrique, S. Z., & Lustgarten, J. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904084 · Cited by 115 · cited 1×
“A recent report suggested that CCL1 could contribute to T reg recruitment in a different tumor model in vivo (35).”
BackgroundNaturally Arising CD25+CD4+ Regulatory T Cells in Tumor Immunity
Nomura, T., & Sakaguchi, S. (2005) · Springer eBooks · doi:10.1007/3-540-27702-1_13 · Cited by 92 · cited 1×
“Expression of PD-L1/B7-H1, an inhibitory ligand that engages the negative regulatory receptor PD-1 on activated T cells (8), and FoxP3, a marker for T regs (26), was examined.”
BackgroundBrown, I. E., Blank, C., Kline, J., Kacha, A. K., & Gajewski, T. F. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.7.4521 · Cited by 91 · cited 1×
“Mechanistic studies have suggested that prevention or reversal of a T cell anergic state can promote tumor rejection in vivo (39–41).”
BackgroundHomeostatic Proliferation Plus Regulatory T-Cell Depletion Promotes Potent Rejection of B16 Melanoma
Kline, J. P., Brown, I. E., Zha, Y.-Y., Blank, C. U., Strickler, J. H., Wouters, H., Zhang, L., & Gajewski, T. F. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4696 · Cited by 89 · cited 3×
“At day 7, tumors and spleens (as control) were harvested and split in two to be either saved in RNAlater (Ambion Inc.) for RT-PCR analysis or used to prepare single-cell suspensions for immediate FACS analysis for CD4, CD8, PD-L1, and FoxP3 as described (6, 48).”
BackgroundMethodChen, S., Pham-Nguyen, K. B., Martinet, O., Huang, Y., Yang, W., Thung, S. N., Chen, L., Mittler, R. S., & Woo, S. L. C. (2000) · Molecular Therapy · doi:10.1006/mthe.2000.0086 · Cited by 87 · cited 1×
“Indeed, preclinical data support the notion that combinatorial manipulation of two immunoregulatory pathways can provide synergy for improved immune-mediated tumor control in vivo (6, 45, 46).”
BackgroundSznol, M., Powderly, J. D., Smith, D. C., Brahmer, J. R., Drake, C. G., McDermott, D. F., Lawrence, D. P., Wolchok, J. D., Topalian, S. L., & Lowy, I. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.15_suppl.2506 · Cited by 85
Frequent cytolytic T-cell responses to peptide MAGE-A10(254-262) in melanoma.
Valmori, D., Dutoit, V., Rubio‐Godoy, V., Chambaz, C., Liénard, D., Guillaume, P., Romero, P. J., Cerottini, J. C., & Rimoldi, D. (2001) · PubMed · Cited by 72
Induction of Cytotoxic Granules in Human Memory CD8+ T Cell Subsets Requires Cell Cycle Progression
Meng, Y., Harlin, H., O’Keefe, J. P., & Gajewski, T. F. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.3.1981 · Cited by 57 · cited 1×
“Purified CD8 + T cells from normal human donors were stimulated with anti-CD3/anti-CD28 mAb-coated beads for 10 days to generate primed effector cells (29).”
MethodBlank, C. A., Brown, I. E., Kacha, A. K., Markiewicz, M. A., & Gajewski, T. F. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.6.3416 · Cited by 34 · cited 1×
“SIY melanoma cells were cultured as described (47).”
MethodGajewski, T. F., Zha, Y., Thurner, B., & Schuler, G. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.9002 · Cited by 31
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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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