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PD-1 blockade induces responses by inhibiting adaptive immune resistance
Open accessAbstract
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells (termed adaptive immune resistance). Here we show that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
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“However, both PDL-1 expression and TMB fail to encapsulate various tumor microenvironmental features influencing ICI responses15–17.”
From Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images (2024) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Pre-treatment CD8+ T cell presence is linked to responses to ICB and anti-PD-1 plus lenvatinib in HCC patients.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [4]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“We compared the tumor-associated immune infiltrates via multi-parameter immunohistochemistry (IHC) and observed a higher density of CD8+ T cells in baseline samples of R versus NR (p=0.04), consistent with prior reports (Fig. 4A and fig. S18) (18, 37).”
From Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients (2018) · cites this paper as [37]
In the citing paper
“Additionally, cancer cells can increase immune checkpoint molecules such as PD-L1, resulting in peripheral T cell exhaustion and the inhibition of malignant cell apoptosis [85].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [85]
In the citing paper
“Indeed, as mentioned in the previous section, both PD-1 and CTLA-4 blockades are more effective in tumors that are infiltrated by T cells or that have high mutation rates and are therefore more immunogenic prior to treatment (86–88).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [88]
In the citing paper
“An increase in CD8+ T cell proliferation within the tumor lesion and an increased frequency of Th9 cells in the patients’ circulation were also associated with treatment response (88, 91, 92).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [88]
In the citing paper
“Other pre-treatment immunological factors associated with improved treatment responses include high eosinophil and lymphocyte blood counts, an abundance of CD8+ T cells infiltrating the tumor or present at the tumor margin, and increased serum TGF-β levels in melanoma patients treated with anti-PD-1 (88, 91, 92, 109).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [88]
In the citing paper
“TILs are therefore under active investigation as a biomarker to guide selection of patients for treatment with ICT, although significant variability exists in definitions and thresholds (149, 150).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [149]
In the citing paper
“The presence of CD8+ T cells at tumor margins and within the tumor prior to treatment with checkpoint inhibitors was associated with a stronger response to treatment (Tumeh et al., 2014).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tumeh et al., 2014
In the citing paper
“abundance of T cells at the invasive tumor margin prior to treatment was associated with a better response, whereas upon treatment, T cell densities were increased both at the margin and within the tumor parenchyma in responding patients”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tumeh et al., 2014
In the citing paper
“In metastatic melanoma patients, a higher density of intratumoral CD8+ T cells at baseline was shown to predict favorable response to anti-PD-1 treatment”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tumeh et al., 2014
In the citing paper
“some studies have found that high TCR diversity in peripheral blood and tumors prior to ICI therapy is predictive of effective treatment, others have pointed to ICI therapy-associated increases in TCR clonality, that is, enrichment of T cells with the same TCRs, as a sign of effective therapy (150, 157-161).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [150]
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Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838
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
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
Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome
Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., Tosolini, M., Camus, M., Berger, A., Wind, P., et al. (2006) · Science · doi:10.1126/science.1129139 · Cited by 6,516
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230
Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma
Hamid, O., Robert, C., DAUD, A. I., Hodi, F. S., Hwu, W., Kefford, R. F., Wolchok, J. D., Hersey, P., Joseph, R. W., Weber, J. S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305133 · Cited by 3,427
Self-citationIntratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., Makrigiannakis, A., Gray, H., Schlienger, K., Liebman, M. N., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa020177 · Cited by 3,397
Wolchok, J. D., Hoos, A., O'Day, S. J., Weber, J. S., Hamid, O., Lebbé, C., Maio, M., Binder, M., Bohnsack, O., Nichol, G. M., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1624 · Cited by 3,214
Cited by
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Items 501–600 of 1,060
Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC
Grant, M. J., Herbst, R. S., & Goldberg, S. B. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00520-1 · Cited by 257
Noman, M. Z., Parpal, S., Van Moer, K., Xiao, M., Yu, Y., Arakelian, T., Viklund, J., De Milito, A., Hasmim, M., Andersson, M., et al. (2020) · Science Advances · doi:10.1126/sciadv.aax7881 · Cited by 255
“This statement is supported by clinical data showing that the presence of preexisting T cells close to the invasive tumor margin is a key determinant to achieving a long-lasting response to anti–PD-1 therapy in melanoma (4).”
Host tissue determinants of tumour immunity
Salmon, H., Remark, R., Gnjatic, S., & Mérad, M. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0125-9 · Cited by 263
Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy
Aval, L. M., Pease, J. E., Sharma, R., & Pinato, D. J. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9103323 · Cited by 253
“The efficacy of ICI appears to correlate with a presence of a pre-existing pro-inflammatory tumour microenvironment (TME) evidenced by higher immune cell infiltration or PD-L1 expression, whereas “immune desert” or “cold” tumours appear to respond less to ICI (TME) [8,9].”
BackgroundInfluentialSucker, A., Zhao, F., Pieper, N., Heeke, C., Maltaner, R., Stadtler, N., Real, B., Bielefeld, N., Howe, S., Weide, B., et al. (2017) · Nature Communications · doi:10.1038/ncomms15440 · Cited by 260
Naing, A., Infante, J. R., Papadopoulos, K. P., Chan, I. H., Shen, C., Ratti, N. P., Rojo, B., Autio, K. A., Wong, D. J. L., Patel, M. R., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.007 · Cited by 258
YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma
Kim, M. H., Kim, C. G., Kim, S.-K., Shin, S. J., Choe, E. A., Park, S.-H., Shin, E.-C., & Kim, J. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0320 · Cited by 241
Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade
Bonavita, E., Bromley, C. P., Jonsson, G., Pelly, V. S., Sahoo, S., Walwyn-Brown, K., Mensurado, S., Moeini, A., Flanagan, E., Bell, C. R., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.10.020 · Cited by 257
“Particularly in immune checkpoint blockade (ICB) therapy, preexisting intratumoral T cell immunity ( Herbst et al., 2014; Tumeh et al., 2014) and activation of specific inflammatory pathways (Ayers et al.”
BackgroundCollier, J. L., Weiss, S. A., Pauken, K. E., Sen, D. R., & Sharpe, A. H. (2021) · Nature Immunology · doi:10.1038/s41590-021-00949-7 · Cited by 237
Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy
Wang, C., Zeng, Q., Gül, Z. M., Wang, S., Pick, R., Cheng, P. F., Bill, R., Wu, Y., Naulaerts, S., Barnoud, C., et al. (2024) · Cell · doi:10.1016/j.cell.2024.04.015 · Cited by 263
Meric‐Bernstam, F., Sweis, R. F., Kasper, S., Hamid, O., Bhatia, S., Dummer, R., Stradella, A., Long, G. V., Spreafico, A., Shimizu, T., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2235 · Cited by 281
Anti-programmed cell death protein-1/ligand-1 therapy in different cancers
Moreno, B. H., & Ribas, A. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.124 · Cited by 252
Self-citationTaube, J. M., Young, G. D., McMiller, T. L., Chen, S., Salas, J. T., Pritchard, T. S., Xu, H., Meeker, A. K., Fan, J., Cheadle, C., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0244 · Cited by 252
A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1
Ngiow, S. F., Young, A., Jacquelot, N., Yamazaki, T., Enot, D., Zitvogel, L., & Smyth, M. J. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1082 · Cited by 237
Inhibitory Receptors Beyond T Cell Exhaustion
Marraco, S. A. F., Neubert, N. J., Verdeil, G., & Speiser, D. E. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00310 · Cited by 250
The Immune Biology of Microsatellite-Unstable Cancer
Kloor, M., & Doeberitz, M. V. K. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.02.004 · Cited by 245
Vilain, R. E., Menzies, A. M., Wilmott, J. S., Kakavand, H., Madore, J., Guminski, A. D., Liniker, E., Kong, B. Y., Cooper, A. J., Howle, J. R., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0698 · Cited by 247
Cardiotoxicity of immune checkpoint inhibitors
Varricchi, G., Galdiero, M. R., Marone, G., Criscuolo, G., Triassi, M., Bonaduce, D., Marone, G., & Tocchetti, C. G. (2017) · ESMO Open · doi:10.1136/esmoopen-2017-000247 · Cited by 247
Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research
Brown, Z. J., Heinrich, B., & Greten, T. F. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0033-6 · Cited by 253
The NKG2A–HLA-E Axis as a Novel Checkpoint in the Tumor Microenvironment
Borst, L., van der Burg, S. H., & van Hall, T. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2095 · Cited by 248
“The unprecedented clinical impact of immune checkpoint blockade therapy induced a new era of cancer treatment (1).”
BackgroundDarb‐Esfahani, S., Kunze, C. A., Kulbe, H., Sehouli, J., Wienert, S., Lindner, J., Budczies, J., Bockmayr, M. L., Dietel, M., Denkert, C., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6429 · Cited by 252
Dynamic versus static biomarkers in cancer immune checkpoint blockade: unravelling complexity
Lesterhuis, W. J., Bosco, A., Millward, M., SMALL, M. P., Nowak, A. K., & Lake, R. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.233 · Cited by 244
Tumour-infiltrating lymphocytes: from prognosis to treatment selection
Brummel, K., Eerkens, A. L., de Bruyn, M., & Nijman, H. W. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-02119-4 · Cited by 259
“Furthermore, trials that evaluated on-treatment histological samples showed that the dynamics in TIL density during treatment was associated with improved outcome, even when there was no association with baseline TILs observed [100, 112].”
BackgroundHudson, K., Cross, N., Jordan-Mahy, N., & Leyland, R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.568931 · Cited by 243
“Patients that initially respond to PD-1/PD-L1-targeted therapy also show “acquired resistance” whereby their tumors display loss of T cell function and/or disrupted antigen processing and presentation (31, 32).”
BackgroundTeng, F., Meng, X., Kong, L., & Yu, J. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.11.014 · Cited by 249
Palmer, C. D., Rappaport, A., Davis, M. J., Hart, M. G., Scallan, C. D., Hong, S., Gitlin, L., Kraemer, L. D., Kounlavouth, S., Yang, A., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01937-6 · Cited by 257
Lv, J., Jia, Y., Li, J., Kuai, W., Li, Y., Guo, F., Xu, X., Zhao, Z., Lv, J., & Li, Z. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1638-6 · Cited by 242
Francis, D. M., Manspeaker, M. P., Schudel, A., Sestito, L. F., O’Melia, M. J., Kissick, H. T., Pollack, B. P., Waller, E. K., & Thomas, S. N. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay3575 · Cited by 240
“Both aCTLA-4 and aPD-1 therapy have also been shown to broaden the repertoire of tumor-specific CD8 T cell clones (15–17), which is associated with improved clinical outcomes (18, 19).”
Mechanisms of immune activation and regulation: lessons from melanoma
Kalaora, S., Nagler, A., Wargo, J. A., & Samuels, Y. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00442-9 · Cited by 252
“Other markers for response to ICIs in melanoma have previously been described, such as the IFNγ signature 138,139 , the presence of T cells in the tumour 130 and the mutational load or predicted neoantigen load 140–142 .”
BackgroundInhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy
Sun, L., Clavijo, P. E., Robbins, Y. L., Patel, P., Friedman, J., Greene, S., Das, R., Silvin, C., Waes, C. V., Horn, L. A., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.126853 · Cited by 239
“We hypothesized that this increase was due to increased IFN production from CD8+ T cells, consistent with the concept of adaptive immune resistance (23).”
BackgroundHui, R., Garon, E. B., Goldman, J. W., Leighl, N. B., Hellmann, M. D., Patnaik, A., Gandhi, L., Eder, J. P., Ahn, M., Horn, L., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx008 · Cited by 239
Hallmarks of response to immune checkpoint blockade
Cogdill, A. P., Andrews, M. C., & Wargo, J. A. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.136 · Cited by 251
Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients
Sullivan, R. J., Hamid, O., Gonzalez, R. C., Infante, J. R., Patel, M. R., Hodi, F. S., Lewis, K. D., Tawbi, H. A., Hernandez, G., Wongchenko, M. J., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0474-7 · Cited by 242
Hopkins, A. C., Yarchoan, M., Durham, J. N., Yusko, E. C., Rytlewski, J. A., Robins, H. S., Laheru, D. A., Le, D. T., Lutz, E. R., & Jaffee, E. M. (2018) · JCI Insight · doi:10.1172/jci.insight.122092 · Cited by 233
“Unlike studies in melanoma (11), we observed no difference in the repertoire of tumor-infiltrating lymphocytes between anti–PD-1 LTS and STS.”
BackgroundResultSelf-citationLearning from clinical trials of neoadjuvant checkpoint blockade
Versluis, J. M., Long, G. V., & Blank, C. U. (2020) · Nature Medicine · doi:10.1038/s41591-020-0829-0 · Cited by 234
Comprehensive T cell repertoire characterization of non-small cell lung cancer
Reuben, A., Zhang, J., Chiou, S.-H., Gittelman, R. M., Li, J., Lee, W.-C., Fujimoto, J., Behrens, C., Liu, X., Wang, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14273-0 · Cited by 220
Self-citationConnors, J. M., Cozen, W., Steidl, C., Carbone, A., Hoppe, R. T., Flechtner, H., & Bartlett, N. L. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-0189-6 · Cited by 245
Buisseret, L., Garaud, S., de Wind, A., den Eynden, G. V., Boisson, A., Solinas, C., Gu‐Trantien, C., Naveaux, C., Lodewyckx, J., Duvillier, H., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1257452 · Cited by 247
Advances in immunotherapy for colorectal cancer: a review
Golshani, G. M., & Zhang, Y. (2020) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756284820917527 · Cited by 252
The Contribution of Epigenetics to Cancer Immunotherapy
Villanueva, L., Álvarez‐Errico, D., & Esteller, M. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.06.002 · Cited by 238
Bhat, A. A., Nisar, S., Singh, M. K., Ashraf, B., Masoodi, T., Prasad, C. P., Sharma, A., Maacha, S., Karedath, T., Hashem, S., et al. (2022) · 癌症：英文版 · doi:10.1002/cac2.12295 · Cited by 251
Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade
Wang, F., Yin, Q., Chen, L., & Davis, M. M. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1712901115 · Cited by 223
Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology
Lee, H. T., Lee, S. H., & Heo, Y. (2019) · Molecules · doi:10.3390/molecules24061190 · Cited by 244
Fatty Acid Oxidation Controls CD8+ Tissue-Resident Memory T-cell Survival in Gastric Adenocarcinoma
Lin, R., Zhang, H., Yuan, Y., He, Q., Zhou, J., Li, S., Sun, Y., Li, D. Y., Qiu, H.-B., Wang, W., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0702 · Cited by 242
“Immune checkpoint blockade unleashes CD8þT cells and enhances their antitumor response in the TME (39).”
BackgroundVirassamy, B., Caramia, F., Savas, P. S., Sant, S. A., Wang, J., Christo, S. N., Byrne, A., Clarke, K. A., Brown, E., Teo, Z. L., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.01.004 · Cited by 247
Chen, Y., Zhang, Y. X., Lv, J.-W., Li, Y.-Q., Wang, Y., He, Q.-M., Yang, X.-J., Sun, Y. H., Mao, Y., Yun, J., et al. (2017) · Theranostics · doi:10.7150/thno.21471 · Cited by 234
Dong, L., Peng, L., Ma, L., Liu, D., Zhang, S., Luo, S.-Z., Rao, J., Zhu, H., Yang, S., Xi, S.-J., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.12.014 · Cited by 237
Girotti, M. R., Gremel, G., Lee, R. J., Galvani, E., Rothwell, D. G., Virós, A., Mandal, A. K., Lim, K. H. J., Saturno, G., Furney, S. J., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1336 · Cited by 235
Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis
Marshall, E. A., Ng, K. W., Kung, S. H. Y., Conway, E. M., Martínez, V. D., Halvorsen, E. C., Rowbotham, D. A., Vucic, E. A., Plumb, A. W., Becker‐Santos, D. D., et al. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0551-1 · Cited by 233
Buisseret, L., Pommey, S., Allard, B., Garaud, S., Bergeron, M., Cousineau, I., Ameye, L., Barèche, Y., Paesmans, M., Crown, J. P., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx730 · Cited by 233
Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology
Jiao, X., Nawab, O., Patel, T. A., Kossenkov, A. V., Halama, N., Jaeger, D., & Pestell, R. G. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1167 · Cited by 239
Weber, J., Gibney, G., Kudchadkar, R., Yu, B., Cheng, P., Martinez, A. J., Kroeger, J., Richards, A., McCormick, L., Moberg, V., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0193 · Cited by 248
Tryptophan-Degrading Enzymes in Tumoral Immune Resistance
van Baren, N., & den Eynde, B. J. V. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00034 · Cited by 237
Beckers, R., Selinger, C. I., Vilain, R. E., Madore, J., Wilmott, J. S., Harvey, K., Holliday, A., Cooper, C. L., Robbins, E., Gillett, D. J., et al. (2015) · Histopathology · doi:10.1111/his.12904 · Cited by 231
Tumour CD274 (PD-L1) expression and T cells in colorectal cancer
Masugi, Y., Nishihara, R., Yang, J., Mima, K., da Silva, A., Shi, Y. X., Inamura, K., Cao, Y., Song, M., Nowak, J. A., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-311421 · Cited by 233
Selby, M., Engelhardt, J., Johnston, R. J., Lu, L.-S., Han, M., Thudium, K. B., Yao, D., Quigley, M. M., Valle, J., Wang, C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161779 · Cited by 236
Wang, S., Campos, J. S., Gallotta, M., Gong, M., Crain, C., Naik, E., Coffman, R. L., & Guiducci, C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608555113 · Cited by 235
Lee, J. M., Lee, M.-H., Garon, E. B., Goldman, J. W., Salehi‐Rad, R., Baratelli, F. E., Schaue, D., Wang, G., Rosen, F., Yanagawa, J., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2821 · Cited by 233
Self-citationBiomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment
van Zyl, B., Tang, D., & Bowden, N. A. (2018) · Endocrine Related Cancer · doi:10.1530/erc-17-0336 · Cited by 234
The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer
Michaelis, K. A., Norgard, M. A., Zhu, X., Levasseur, P. R., Sivagnanam, S., Liudahl, S. M., Burfeind, K. G., Olson, B. G., Pelz, K. R., Ramos, D. M. A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12657-w · Cited by 231
Mutational Landscape and Sensitivity to Immune Checkpoint Blockers
Chabanon, R. M., Pedrero, M., Lefèbvre, C., Marabelle, A., Soria, J., & Postel-Vinay, S. C. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0903 · Cited by 236
Novel technologies and emerging biomarkers for personalized cancer immunotherapy
Yuan, J. D., Hegde, P. S., Clynes, R., Foukas, P. G., Harari, A., Kleen, T. O., Kvistborg, P., Maccalli, C., Maecker, H. T., Page, D. B., et al. (2016) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-016-0107-3 · Cited by 235
Self-citationIdentifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy
Gnjatic, S., Bronte, V., Brunet, L. R., Butler, M. O., Disis, M. L., Galon, J., Håkansson, L., Hanks, B. A., Karanikas, V., Khleif, S. N., et al. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0243-4 · Cited by 235
Etzerodt, A., Tsalkitzi, K., Maniecki, M. B., Damsky, W., Delfini, M., Baudoin, E., Moulin, M., Bosenberg, M., Graversen, J. H., Auphan‐Anezin, N., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20182124 · Cited by 242
“Blocking PD-1/PD-L1 signaling using anti–PD-1 or PD-L1 antibodies thus leads to increased CTL activation, ultimately resulting in unprecedented rates of tumor regression (Tumeh et al., 2014).”
BackgroundWard, J. P., Gubin, M. M., & Schreiber, R. D. (2016) · Advances in immunology · doi:10.1016/bs.ai.2016.01.001 · Cited by 232
González, R. S., Salaria, S. N., Bohannon, C. D., Huber, A. R., Feely, M. M., & Shi, C. (2016) · Histopathology · doi:10.1111/his.13118 · Cited by 228
Tumor Mutation Burden: Leading Immunotherapy to the Era of Precision Medicine?
Steuer, C. E., & Ramalingam, S. S. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.8770 · Cited by 228
Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression
Hossain, D. M. S., Javaid, S., Cai, M., Zhang, C., Sawant, A., Hinton, M., Sathe, M., Grein, J., Blumenschein, W., Pinheiro, E. M., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci94586 · Cited by 216
Riesenberg, S., Groetchen, A., Siddaway, R., Bald, T., Reinhardt, J., Smorra, D., Sirokay, J. D., Renn, M., Phung, B., Aymans, P., et al. (2015) · Nature Communications · doi:10.1038/ncomms9755 · Cited by 238
MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells
Limagne, E., Nuttin, L., Thibaudin, M., Jacquin, É., Aucagne, R., Bon, M., Revy, S., Barnestein, R., Ballot, E., Truntzer, C., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2021.12.009 · Cited by 231
Subudhi, S. K., Aparicio, A., Gao, J., Zurita, A. J., Araujo, J. C., Logothetis, C. J., Tahir, S. A., Korivi, B. R., Slack, R. S., Vence, L., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611421113 · Cited by 226
Self-citationMcArthur, H. L., Diab, A. K., Page, D. B., Yuan, J. D., Solomon, S. B., Sacchini, V., Comstock, C., Durack, J. C., Maybody, M., Sung, J. S., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0190 · Cited by 230
Kakavand, H., Jackett, L. A., Menzies, A. M., Gide, T. N., Carlino, M. S., Saw, R. P. M., Thompson, J. F., Wilmott, J. S., Long, G. V., & Scolyer, R. A. (2017) · Modern Pathology · doi:10.1038/modpathol.2017.89 · Cited by 230
Aoki, T., Chong, L. C., Takata, K., Milne, K., Hav, M., Colombo, A., Chavez, E. A., Nissen, M. D., Wang, X., Miyata‐Takata, T., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0680 · Cited by 233
“Inhibitory receptor–mediated immune tolerance that can be hijacked by tumors has been a major target of cancer immunotherapy (23, 24).”
BackgroundWang, G., Kang, X., Chen, K. S., Jehng, T., Jones, L. E., Chen, J., Huang, X. F., & Chen, S. (2020) · Nature Communications · doi:10.1038/s41467-020-15229-5 · Cited by 232
Khoja, L., Butler, M. O., Kang, S. P., Ebbinghaus, S., & Joshua, A. M. (2015) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-015-0078-9 · Cited by 235
An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis
Kim, J. W., Lee, J.-Y., Oh, M., & Lee, E. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01077-y · Cited by 251
Kawazoe, A., Kuwata, T., Kuboki, Y., Shitara, K., Nagatsuma, A. K., Aizawa, M., Yoshino, T., Doi, T., Ohtsu, A., & Ochiai, A. (2016) · Gastric Cancer · doi:10.1007/s10120-016-0631-3 · Cited by 229
Martin, C. J., Datta, A., Littlefield, C., Kalra, A., Chapron, C., Wawersik, S., Dagbay, K. B., Brueckner, C. T., Nikiforov, A., Danehy, F. T., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay8456 · Cited by 224
Overcoming Immune Evasion in Melanoma
Eddy, K., & Chen, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238984 · Cited by 243
(2017) · doi:10.1158/2159-8290.cd-17-0256 · Cited by 223
Self-citationGorris, M. A. J., Halilović, A., Rabold, K., van Duffelen, A., Wickramasinghe, I. N. A., Verweij, D. I., Wortel, I. M. N., Textor, J. C., de Vries, I. J. M., & Figdor, C. G. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1701262 · Cited by 225
Electromagnetic Nanomedicines for Combinational Cancer Immunotherapy
Li, J., Luo, Y., & Pu, K. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202008386 · Cited by 223
Sun, Z., Ren, Z., Yang, K., Liu, Z., Cao, S., Deng, S., Xu, L., Liang, Y., Guo, J., Bian, Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11782-w · Cited by 211
Burugu, S., Asleh, K., & Nielsen, T. O. (2016) · Breast Cancer · doi:10.1007/s12282-016-0698-z · Cited by 234
CAR T‐cell therapy of solid tumors
Yong, C. S. M., Dardalhon, V., Devaud, C., Taylor, N. N., Darcy, P. K., & Kershaw, M. H. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.128 · Cited by 226
Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia
Ghorani, E., Kaur, B. S., Fisher, R. A., Short, D., Joneborg, U., Carlson, J. W., Akarca, A. U., Marafioti, T., Quezada, S. A., Sarwar, N., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32894-5 · Cited by 221
Diab, A., Tannir, N. M., Bentebibel, S.-E., Hwu, P., Papadimitrakopoulou, V., Haymaker, C., Kluger, H. M., Gettinger, S. N., Sznol, M., Tykodi, S. S., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1510 · Cited by 237
“High CD8+ tumor density is reportedly predictive for response to PD-1 blockade (9), with”
BackgroundVillarroel‐Espíndola, F., Yu, X., Datar, I. J., Mani, N. L., Sanmamed, M. F., Velcheti, V., Syrigos, K., Toki, M. I., Zhao, H., Chen, L., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2542 · Cited by 226
Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity
Hoves, S., Ooi, C.-H., Wolter, C., Sade, H., Bissinger, S., Schmittnaegel, M., Ast, O., Giusti, A. M., Wartha, K., Runza, V., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171440 · Cited by 224
Conniot, J., Scomparin, A., Peres, C., Yeini, E., Pozzi, S., Matos, A. I., Kleiner, R., Moura, L. I. F., Zupančič, E., Viana, A. S., et al. (2019) · Nature Nanotechnology · doi:10.1038/s41565-019-0512-0 · Cited by 217
Vadakekolathu, J. N., Minden, M. D., Hood, T., Church, S., Reeder, S., Altmann, H., Sullivan, A. H., Viboch, E., Patel, T., Ibrahimova, N., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz0463 · Cited by 218
Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
Phillips, D. J., Matusiak, M., Rivero‐Gutiérrez, B., Bhate, S. S., Barlow, G. L., Jiang, S., Demeter, J., Smythe, K. S., Pierce, R. H., Fling, S. P., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26974-6 · Cited by 230
Self-citationResistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next?
Welsh, S. J., Rizos, H., Scolyer, R. A., & Long, G. V. (2016) · European Journal of Cancer · doi:10.1016/j.ejca.2016.04.005 · Cited by 224
Meyer, M. A., Baer, J. M., Knolhoff, B. L., Nywening, T. M., Panni, R. Z., Su, X., Weilbaecher, K. N., Hawkins, W. G., Ma, C. X., Fields, R. C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03600-6 · Cited by 228
Buder‐Bakhaya, K., & Hassel, J. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01474 · Cited by 219
Advancing to the era of cancer immunotherapy
Wang, Y., Wang, M., Wu, H., & Xu, R. (2021) · 癌症：英文版 · doi:10.1002/cac2.12178 · Cited by 221
Stem-like exhausted and memory CD8+ T cells in cancer
Gebhardt, T., Park, S. L., & Parish, I. A. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00615-0 · Cited by 234
Granier, C., Dariane, C., Combe, P., Verkarre, V., Urien, S., Badoual, C., Roussel, H., Mandavit, M., Ravel, P., Sibony, M., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0274 · Cited by 224
Tada, Y., Togashi, Y., Kotani, D., Kuwata, T., Sato, E., Kawazoe, A., Doi, T., Wada, H., Nishikawa, H., & Shitara, K. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0403-1 · Cited by 224
Metadata
- Authors
- Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., West, A. N., Carmona, M., Kivork, C., Seja, E., Cherry, G., Gutierrez, A. J., Grogan, T. R., Mateus, C., Tomasic, G., Glaspy, J. A., Emerson, R. O., Robins, H., Pierce, R. H., Elashoff, D. A., Robert, C., & Ribas, A.
- Affiliations
- University of California, Los Angeles (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Inserm (FR)
- Adaptive Biotechnologies (United States) (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Tumeh, Paul C.
- Ribas, Antoni
- ORCID
- Venue
- Nature
- Published
- 2014-11-26
- Volume
- 515
- Issue
- 7528
- Pages
- 568-571
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4246418
- OpenAlex
- W2039123767
- Semantic Scholar
- 2c96ca62d538ff43fce01bc848fc018f6ae2b4a0
- Cited by
- 6,609
- References
- 24
- Citations by year
- 2026: 280 · 2025: 398 · 2024: 491 · 2023: 588 · 2022: 695 · 2021: 768 · 2020: 800 · 2019: 610 · 2018: 593 · 2017: 566 · 2016: 488 · 2015: 303 · 2014: 12
- FWCI
- 220.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Association for Cancer Research (SU2C-AACR-DT1012)
- Cancer Research Institute (SU2C-AACR-DT1012, CA16042)
- Melanoma Research Alliance (SU2C-AACR-DT1012)
- Adaptive Biotechnologies
- Institut Gustave-Roussy
- Sociedad Española de Oncología Médica
- National Institutes of Health (UL1TR000124, 5u54ca119347-03, P30 CA- 16042, SU2C-AACR-DT1012, CA16042)
- Stand Up To Cancer (SU2C-AACR-DT1012))
- National Cancer Institute (U54-CA119347, P01CA168585, P30-CA16042, R01CA170689, P30CA016042)
- National Institute of Allergy and Infectious Diseases (K08AI091663)
- National Center for Advancing Translational Sciences
- 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
- pembrolizumab, adaptive immune resistance, CD8+ T cells, PD-L1, PD-1/PD-L1 axis, metastatic melanoma, tumor-infiltrating lymphocytes, T cell receptor repertoire, predictive biomarkers, tumor regression, immune checkpoint inhibitors
- MeSH terms
- Aged, Aged, 80 and over, Female, Humans, Immunotherapy, Male, Melanoma, Middle Aged, Models, Biological, Biomarkers, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Treatment Outcome, CD8-Positive T-Lymphocytes, Cell Proliferation, Adaptive Immunity, Programmed Cell Death 1 Receptor
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