The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Flagged first, then by citations
Cited by
Sorted by citations
Items 801–900 of 1,060
Böhm, S., Montfort, A., Pearce, O. M. T., Topping, J. H., Chakravarty, P., Everitt, G. L. A., Clear, A. J., McDermott, J. R., Ennis, D. P., Dowe, T., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2657 · Cited by 160
T-cell receptor-engineered T cells for cancer treatment: current status and future directions
Yü, P., Liu, C., & Zhang, Y. (2017) · Protein & Cell · doi:10.1007/s13238-016-0367-1 · Cited by 161
Reinhardt, J., Landsberg, J., Schmid-Burgk, J. L., Ramis, B. B., Bald, T., Glodde, N., Lopez-Ramos, D., Young, A., Ngiow, S. F., Nettersheim, D., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0395 · Cited by 167
Self-citationMSH2 Loss in Primary Prostate Cancer
Guedes, L. B., Antonarakis, E. S., Schweizer, M. T., Mirkheshti, N., Almutairi, F., Park, J. C., Glavaris, S. A., Hicks, J. L., Eisenberger, M. A., Marzo, A. M. D., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0955 · Cited by 158
Cancer Cell-Intrinsic PD-1 and Implications in Combinatorial Immunotherapy
Yao, H., Wang, H., Li, C., Fang, J.-Y., & Xu, J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01774 · Cited by 141
Lim, S., Park, J., Shim, M. K., Um, W., Yoon, H. Y., Ryu, J. H., Lim, D., & Kim, K. (2019) · Theranostics · doi:10.7150/thno.38425 · Cited by 162
“Clinical studies have shown that only a fraction (10-38%) of cancer patients respond to current treatment using immune checkpoint inhibitors [27-31].”
BackgroundKim, J. Y., Kronbichler, A., Eisenhut, M., Hong, S. H., van der Vliet, H. J., Kang, J., Shin, J. I., & Gamerith, G. (2019) · Cancers · doi:10.3390/cancers11111798 · Cited by 158
Current Achievements and Applications of Transcriptomics in Personalized Cancer Medicine
Supplitt, S., Karpiński, P., Sasiadek, M. M., & Łaczmańska, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031422 · Cited by 166
“This landscape of TCRs/BCRs may serve as a predictive biomarker of the effectiveness of immunotherapy [201,202].”
BackgroundNanomedicine‐Boosting Tumor Immunogenicity for Enhanced Immunotherapy
Huang, J., Yang, B., Peng, Y., Huang, J., Wong, S. H. D., Bian, L., Zhu, K., Shuai, X., & Han, S. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202011171 · Cited by 160
Coutzac, C., Adam, J., Soularue, É., Collins, M., Racine, A., Mussini, C., Boselli, L., Kamsu-Kom, N., Mateus, C., Charrier, M., et al. (2017) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjx081 · Cited by 158
Self-citationUpdate on Immunohistochemistry for the Diagnosis of Lung Cancer
Inamura, K. (2018) · Cancers · doi:10.3390/cancers10030072 · Cited by 167
PD-L1 blockade enhances anti-tumor efficacy of NK cells
Oyer, J. L., Gitto, S. B., Altomare, D. A., & Copik, A. J. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1509819 · Cited by 160
Hogan, S. A., Courtier, A., Cheng, P. F., Jaberg-Bentele, N. F., Goldinger, S. M., Manuel, M., Perez, S., Plantier, N., Mouret, J.-F., Nguyen‐Kim, T. D. L., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0136 · Cited by 155
Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1
Leclerc, M., Voilin, E., Gros, G., Corgnac, S., de Montpréville, V., Validire, P., Bismuth, G., & Mami‐Chouaib, F. (2019) · Nature Communications · doi:10.1038/s41467-019-11280-z · Cited by 155
Bystander T cells in cancer immunology and therapy
Meier, S. L., Satpathy, A. T., & Wells, D. K. (2022) · Nature Cancer · doi:10.1038/s43018-022-00335-8 · Cited by 162
Tu, L., Guan, R., Yang, H., Zhou, Y., Hong, W., Ma, L., Zhao, G., & Yu, M. (2020) · International Journal of Cancer · doi:10.1002/ijc.32785 · Cited by 167
“Previous studies showed that increased release of PD-1 from activated T cells could promote T cell proliferation and enhance T cell effector functions.(16) Considering the complexity of the tumor microenvironment, PD-1 alonemay not indicate the immunosuppressive or activated status of the immune response.”
ResultCancer immune contexture and immunotherapy
Becht, É., Giraldo, N. A., Dieu‐Nosjean, M., Sautès‐Fridman, C., & Fridman, W. H. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.11.009 · Cited by 159
Akalu, Y. T., Rothlin, C. V., & Ghosh, S. (2017) · Immunological Reviews · doi:10.1111/imr.12522 · Cited by 158
Belgiovine, C., Bello, E., Liguori, M., Craparotta, I., Mannarino, L., Paracchini, L., Beltrame, L., Marchini, S., Galmarini, C. M., Mantovani, A., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.205 · Cited by 156
Trial watch: Peptide-based vaccines in anticancer therapy
Bezu, L., Kepp, O., Cerrato, G., Pol, J. G., Fucikova, J. P., Špíšek, R., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1511506 · Cited by 158
Yin, Z., Yu, M., Ma, T., Zhang, C., Huang, S., Karimzadeh, M. R., Momtazi‐Borojeni, A. A., & Chen, S. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001698 · Cited by 156
Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma
Deken, M. A., Gadiot, J., Jordanova, E. S., Lacroix, R., van Gool, M. M. J., Kroon, P., Pineda, C., Foppen, M. H. G., Scolyer, R. A., Song, J., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1238557 · Cited by 155
Systematic Pan-Cancer Analysis Reveals Immune Cell Interactions in the Tumor Microenvironment
Varn, F. S., Wang, Y., Mullins, D. W., Fiering, S., & Cheng, C. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2490 · Cited by 159
Using T Cell Receptor Repertoires to Understand the Principles of Adaptive Immune Recognition
Bradley, P. H., & Thomas, P. G. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041757 · Cited by 162
Guzik, K., Tomala, M. D., Muszak, D., Konieczny, M., Hec, A., Tyrcha, U., Pustuła, M., Butera, R., Dömling, A. S. S., & Holak, T. A. (2019) · Molecules · doi:10.3390/molecules24112071 · Cited by 159
Nixon, A. B., Schalper, K. A., Jacobs, I. A., Potluri, S., Wang, I., & Fleener, C. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0799-2 · Cited by 154
“The results of TCR sequencing of tumor samples has also predicted response to pembrolizumab treatment [1], with higher baseline TCR clonality in tumors from responding patients with melanoma observed in a recent study.”
BackgroundZhang, J., Ji, Z., Caushi, J. X., Asmar, M. E., Anagnostou, V., Cottrell, T. R., Chan, H. Y., Suri, P., Guo, H., Merghoub, T., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2931 · Cited by 150
“In addition to PD-L1 expression (8), other immune correlates of clinical response to PD-1 blockade include CD8þ T-cell infiltration (9), the presence of PD-1þCD8þ T cells at the invasive tumor margin (9, 10), high densities of CD45ROþgranzymeþ T cells (11), IFNg-associated gene expression (12), the proximity of PD1þ t…”
BackgroundPD-L1 status in breast cancer: Current view and perspectives
Vranić, S., Cyprian, F. S., Gatalica, Z., & Palazzo, J. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.12.003 · Cited by 158
Ferrarotto, R., Amit, M., Nagarajan, P., Rubin, M., Yuan, Y., Bell, D., El‐Naggar, A. K., Johnson, J. M., Morrison, W. H., Rosenthal, D. I., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0585 · Cited by 161
“These findings are in concordance with previous studies in which responses to targeting the PD-1/PD-L1 axis were associated with higher CD8þ T-cell densities and Th1-type gene expression in melanoma, lung, and other cancers (29, 30).”
ResultCXCR4 Ligands: The Next Big Hit?
Walenkamp, A., Lapa, C., Herrmann, K., & Wester, H. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.186874 · Cited by 156
Low-Dose Anti-Angiogenic Therapy Sensitizes Breast Cancer to PD-1 Blockade
Li, Q., Wang, Y., Jia, W., Deng, H., Li, G., Deng, W., Chen, J., Kim, B. Y. S., Jiang, W., Liu, Q., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2179 · Cited by 156
KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance
Zavitsanou, A., Pillai, R., Yuan, H., Wu, W., Bartnicki, E., Karakousi, T. R., Rajalingam, S., Herrera, A. M., Karatza, A., Rashidfarrokhi, A., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113295 · Cited by 157
“9,91 Although DCs were primarily studied for their ability to prime T cells in the lymph nodes, they are now also recognized as key players at the primary tumor site.”
BackgroundFang, D. D., Tang, Q., Kong, Y., Wang, Q., Gu, J., Fang, X., Zou, P., Rong, T., Wang, J., Yang, D., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0750-6 · Cited by 151
Lesokhin, A. M., Callahan, M. K., Postow, M. A., & Wolchok, J. D. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.3010274 · Cited by 158
Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection?
Festino, L., Botti, G., Lorigan, P. C., Masucci, G. V., Hipp, J., Horak, C. E., Melero, I., & Ascierto, P. A. (2016) · Drugs · doi:10.1007/s40265-016-0588-x · Cited by 149
Kluger, H. M., Zito, C. R., Turcu, G., Baine, M. K., Zhang, H., Adeniran, A., Sznol, M., Rimm, D. L., Kluger, Y., Chen, L., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3146 · Cited by 155
Mohme, M., Schliffke, S., Maire, C. L., Rünger, A., Glau, L., Mende, K. C., Matschke, J., Gehbauer, C., Akyüz, N., Zapf, S., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2617 · Cited by 152
Opzoomer, J. W., Sosnowska, D., Anstee, J. E., Spicer, J. F., & Arnold, J. N. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01654 · Cited by 155
“Unprecedented clinical benefit has been achieved in a variety of cancers using Immune checkpoint inhibitors (ICIs) that targets immune regulation of T-cell responses, such as antibodies which neutralize PD-1 or its ligand PD-L1, or CTLA-4 (11).”
BackgroundInfluentialSirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells
Hamaidi, I., Zhang, L., Kim, N., Wang, M.-H., Iclozan, C., Fang, B., Liu, M., Koomen, J. M., Berglund, A., Yoder, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.07.008 · Cited by 148
“PD-1 is paradoxically a marker of activated tumor-reactive CD8+ T cells in melanoma, and tumor regression with PD-1 blockade requires pre-existing PD-1+ CD8+ T cells (Tumeh et al., 2014).”
BackgroundGranzymes: The Molecular Executors of Immune-Mediated Cytotoxicity
Hay, Z. L. Z., & Slansky, J. E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031833 · Cited by 172
“T cells mediate their cytotoxic function through multiple mechanisms, which is of particular interest given the advancements in immunotherapies [4,5].”
BackgroundFoote, J. B., Kok, M., Leatherman, J. M., Armstrong, T. D., Marcinkowski, B. C., Ojalvo, L. S., Kanne, D. B., Jaffee, E. M., Dubensky, T. W., & Emens, L. A. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0284 · Cited by 156
Genomics and emerging biomarkers for immunotherapy of colorectal cancer
Kather, J. N., Halama, N., & Jaeger, D. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.02.010 · Cited by 154
High-throughput single-сell sequencing in cancer research
Jia, Q., Chu, H., Jin, Z., Long, H., & Zhu, B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00990-4 · Cited by 157
Colorectal cancer immunotherapy-Recent progress and future directions
Zhao, W., Jin, L., Chen, P., Li, D., Gao, W., & Dong, G. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215816 · Cited by 159
Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors
Simpson, R. C., Shanahan, E. R., Scolyer, R. A., & Long, G. V. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00803-9 · Cited by 153
Wu, S.-P., Liao, R.-Q., Tu, H., Wang, W., Dong, Z., Huang, S., Guo, W., Gou, L.-Y., Sun, H., Zhang, Q., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.11.132 · Cited by 154
Zhu, J., Armstrong, A. J., Friedlander, T. W., Kim, W. K., Pal, S. K., George, D. J., & Zhang, T. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0314-1 · Cited by 149
Agdashian, D., ElGindi, M., Xie, C., Sandhu, M., Pratt, D. W., Kleiner, D. E., Figg, W. D., Rytlewski, J. A., Sanders, C. M., Yusko, E. C., et al. (2019) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-019-02299-8 · Cited by 150
“In addition, T-cell receptor sequencing data from tumor infiltrating cells revealed a similar pattern of high tumor clonality and T-cell fractions in tumor biopsies derived from patients responding to immune checkpoint blockade therapy comparable to a pattern, which has been previously described in immunosequenced mel…”
MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma
van Velzen, M. J. M., Derks, S., van Grieken, N. C. T., Mohammad, N. H., & van Laarhoven, H. W. M. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102024 · Cited by 148
Zheng, H., Liu, H., Ge, Y., & Wang, X. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02252-9 · Cited by 153
Hwang, M., Canzoniero, J. V., Rosner, S., Zhang, G., White, J. R., Belcaid, Z., Cherry, C., Balan, A., Pereira, G., Curry, A., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004688 · Cited by 150
Seifert, A. M., Zeng, S., Zhang, J. Q., Kim, T. S., Cohen, N. A., Beckman, M. J., Medina, B. D., Maltbaek, J. H., Loo, J. K., Crawley, M. H., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1163 · Cited by 149
Ma, C., Patel, K., Singhi, A. D., Ren, B., Zhu, B., Shaikh, F. Y., & Sun, W. (2016) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000698 · Cited by 150
Moreno, B. H., Zaretsky, J. M., García-Díaz, Á., Tsoi, J., Parisi, G., Robert, L., Meeth, K. M., Ndoye, A., Bosenberg, M., Weeraratna, A. T., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0060 · Cited by 151
Self-citationPVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function
Whelan, S., Ophir, E., Kotturi, M. F., Levy, O., Ganguly, S., Leung, L., Vaknin, I., Kumar, S., Dassa, L., Hansen, K., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0442 · Cited by 149
Rational combinations of immunotherapy with radiotherapy in ovarian cancer
Herrera, F. G., Irving, M. B., Kandalaft, L. E., & Coukos, G. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30401-2 · Cited by 154
Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma
Algazi, A. P., Twitty, C., Tsai, K. K., Le, M. H., Pierce, R. H., Browning, E., Hermiz, R., Canton, D. A., Bannavong, D., Oglesby, A., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2217 · Cited by 154
Self-citationZhu, G., Su, H., Johnson, C. H., Khan, S. A., Kluger, H. M., & Lu, L. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.03.053 · Cited by 150
Oguejiofor, K., Hall, J., Slater, C., Betts, G. N. J., Hall, G. L., Slevin, N. J., Dovedi, S. J., Stern, P. L., & West, C. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.277 · Cited by 149
Biomarkers in Cancer Immunotherapy
Schumacher, T. N., Keşmir, C., & van Buuren, M. M. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.12.004 · Cited by 149
The role of immune checkpoint inhibition in the treatment of ovarian cancer
Gaillard, S. L., Secord, A. A., & Monk, B. J. (2016) · Gynecologic Oncology Research and Practice · doi:10.1186/s40661-016-0033-6 · Cited by 149
Predictive Modeling of Influenza Shows the Promise of Applied Evolutionary Biology
Morris, D. H., Gostic, K. M., Pompei, S., Bedford, T., Łuksza, M., Neher, R. A., Grenfell, B. T., Lässig, M., & McCauley, J. W. (2017) · Trends in Microbiology · doi:10.1016/j.tim.2017.09.004 · Cited by 148
PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy
Zamarin, D., Ricca, J. M., Sadekova, S., Oseledchyk, A., Yu, Y., Blumenschein, W. M., Wong, J., Gigoux, M., Merghoub, T., & Wolchok, J. D. (2018) · Journal of Clinical Investigation · doi:10.1172/jci98047 · Cited by 151
Immune checkpoint inhibitors in cancer therapy
Eika, S., Peng, L., Renato, B., Nicholas, R., Ming, Y., & Yaohe, W. (2018) · The Journal of Biomedical Research · doi:10.7555/jbr.31.20160168 · Cited by 119
Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor
Koblish, H. K., Wu, L., Wang, L.-C. S., Liu, P. C. C., Wynn, R., Rios‐Doria, J., Spitz, S., Liu, H., Volgina, A., Zolotarjova, N., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1156 · Cited by 155
Gatalica, Z., Vranic, S., Xiu, J., Swensen, J., & Reddy, S. (2016) · Familial Cancer · doi:10.1007/s10689-016-9884-6 · Cited by 141
IL-27 induces the expression of IDO and PD-L1 in human cancer cells
Carbotti, G., Barisione, G., Airoldi, I., Mezzanzanica, D., Bagnoli, M., Ferrero, S., Petretto, A., Fabbi, M., & Ferrini, S. (2015) · Oncotarget · doi:10.18632/oncotarget.6530 · Cited by 147
Palakurthi, S. S., Kuraguchi, M., Zacharek, S. J., Zudaire, E., Huang, W., Bonal, D. M., Liu, J., Dhaneshwar, A., DePeaux, K., Gowaski, M. R., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0595 · Cited by 145
“Anti–PD-1 treatment resulted in increased clonality, reflecting a focusing of preexisting T-cell responses, as previously reported in both preclinical and clinical settings (36, 44).”
BackgroundLong-distance modulation of bystander tumor cells by CD8+ T-cell-secreted IFN-γ
Hoekstra, M. E., Bornes, L., Dijkgraaf, F. E., Philips, D., Pardieck, I. N., Toebes, M., Thommen, D. S., van Rheenen, J., & Schumacher, T. N. (2020) · Nature Cancer · doi:10.1038/s43018-020-0036-4 · Cited by 145
Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1
Ye, Y., Kuang, X., Xie, Z., Liang, L., Zhang, Z., Zhang, Y., Ma, F., Gao, Q., Chang, R., Lee, H., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-00780-z · Cited by 145
“ICB therapies that target cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) [2], programmed death 1 (PD-1) [3], and its ligand programmed death ligand 1 (PD-L1) [4] have shown promising clinical effects.”
Wang, T., Cai, S., Cheng, Y., Zhang, W., Wang, M., Sun, H., Guo, B., Li, Z., Xiao, Y., & Jiang, S. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01682 · Cited by 149
Kakavand, H., Wilmott, J. S., Menzies, A. M., Vilain, R. E., Haydu, L. E., Yearley, J. H., Thompson, J. F., Kefford, R. F., Hersey, P., Long, G. V., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2023 · Cited by 148
Self-citationOck, C.-Y., Kim, S., Keam, B., Kim, M., Kim, T. M., Kim, J.-H., Jeon, Y. K., Lee, J., Kwon, S. K., Hah, J. H., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7431 · Cited by 150
Sloan, E. A., Ring, K. L., Willis, B. C., Modesitt, S. C., & Mills, A. M. (2016) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000783 · Cited by 146
Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment
Wang, Q., & Wu, X. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.03.015 · Cited by 146
Lazăr, D. C., Avram, M. F., Romosan, I., Cornianu, M., Tăban, S. M., & Goldiș, A. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i32.3583 · Cited by 146
Strategies based on metal-based nanoparticles for hypoxic-tumor radiotherapy
Zhang, C., Yan, L., Gu, Z., & Zhao, Y. (2019) · Chemical Science · doi:10.1039/c9sc02107h · Cited by 146
CXCL11 Correlates With Antitumor Immunity and an Improved Prognosis in Colon Cancer
Cao, Y., Jiao, N., Sun, T., Ma, Y., Zhang, X., Chen, H., Hong, J., & Zhang, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.646252 · Cited by 147
Tumor-intrinsic oncogene pathways mediating immune avoidance
Spranger, S., & Gajewski, T. F. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1086862 · Cited by 154
Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients
Xing, X., Guo, J., Ding, G., Li, B., Dong, B., Feng, Q. F., Shen, L., Zhang, J., Ying, X., Cheng, X., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1356144 · Cited by 147
Teh, J. L. F., & Aplin, A. E. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1967 · Cited by 148
Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance
Muraoka, D., Seo, N., Hayashi, T., Tahara, Y., Fujii, K., Tawara, I., Miyahara, Y., Okamori, K., Yagita∥, H., Imoto, S., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci97642 · Cited by 147
Song, H., Yang, P., Huang, P., Zhang, C., Kong, D., & Wang, W. (2019) · Theranostics · doi:10.7150/thno.30577 · Cited by 148
“Another mechanism by which cancer limits the host immune response is via upregulation of PD-L1 and PD-L2 that is associated with PD-L1 expression [62-64].”
BackgroundMsaouel, P., Malouf, G. G., Su, X., Yao, H., Tripathi, D. N., Soeung, M., Gao, J., Rao, P., Coarfa, C., Creighton, C. J., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2020.04.002 · Cited by 148
“This approach can help distinguish tumor cells from immune cells and thus allow reliable PD-L1 immune quantification on different cell subsets as previously established (Herbst et al., 2014; Tumeh et al., 2014; Twyman-Saint Victor et al., 2015).”
Liu, Q., Wang, C., Zheng, Y., Zhao, Y., Wang, Y., Hao, J., Zhao, X., Yi, K., Shi, L., Kang, C., et al. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120275 · Cited by 144
Role of CD8+ T lymphocyte cells: Interplay with stromal cells in tumor microenvironment
Xie, Q., Ding, J. P., & Chen, Y. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.03.027 · Cited by 155
Briere, D. M., Sudhakar, N., Woods, D. M., Hallin, J. F., Engstrom, L. D., Aranda, R., Chiang, H., Sodré, A. L., Olson, P., Weber, J. S., et al. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2091-y · Cited by 149
PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation
Qiu, X. Y., Hu, D. X., Chen, W., Chen, R. Q., Shi, Q., Li, C. Y., Li, Y. J., Xiong, X., Liu, D., Pan, F., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.03.002 · Cited by 151
The clinical promise of immunotherapy in triple-negative breast cancer
Vikas, P., Borcherding, N. C., & Zhang, W. (2018) · Cancer Management and Research · doi:10.2147/cmar.s185176 · Cited by 147
Cader, F. Z., Hu, X. S., Goh, W. L., Wienand, K., Ouyang, J., Mandato, E., Redd, R. A., Lawton, L. N., Chen, P.-H., Weirather, J. L., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-1006-1 · Cited by 145
circFAT1 Promotes Cancer Stemness and Immune Evasion by Promoting STAT3 Activation
Jia, L., Wang, Y., & Wang, C. (2021) · Advanced Science · doi:10.1002/advs.202003376 · Cited by 145
Hallmarks of Resistance to Immune-Checkpoint Inhibitors
Karasarides, M., Cogdill, A. P., Robbins, P. B., Bowden, M., Burton, E. M., Butterfield, L. H., Cesano, A., Hammer, C., Haymaker, C., Horak, C. E., et al. (2022) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0586 · Cited by 154
“In adaptive resistance, IFNg can potentially compromise antitumor immunity by directly upregulating both PD-L1 and PD-L2 on tumor and immune cells (48, 89, 90) and can drive resistance to checkpoint blockade by PD-L1–dependent and –independent mechanisms (91).”
BackgroundWabitsch, S., McCallen, J., Kamenyeva, O., Ruf, B., McVey, J. C., Kabát, J., Walz, J. S., Rotman, Y., Bauer, K. C., Craig, A. J., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.03.010 · Cited by 147
Dammeijer, F. F., Lievense, L. A., Kaijen-Lambers, M. E. H., van Nimwegen, M., Bezemer, K., Hegmans, J. P., van Hall, T., Hendriks, R. W., & Aerts, J. G. J. V. (2017) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0309 · Cited by 144
Jiang, Y., Xie, J., Han, Z., Liu, W., Xi, S., Huang, L., Huang, W., Lin, T., Zhao, L., Hu, Y., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0848 · Cited by 143
Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer
Gray, J. E., Saltos, A. N., Tanvetyanon, T., Haura, E. B., Creelan, B., Antonia, S. J., Shafique, M. R., Zheng, H., Dai, W., Saller, J. J., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1305 · Cited by 140
“Gene expression changes in tumor biopsies A transition toward a more immunogenic tumor microenvironment is associatedwith ICI responses inmelanoma (5, 6).”
BackgroundMethodInfluentialPreclinical murine tumor models: A structural and functional perspective
Guérin, M. V., Finisguerra, V., den Eynde, B. J. V., Bercovici, N., & Trautmann, A. (2020) · eLife · doi:10.7554/elife.50740 · Cited by 160
Vascular normalisation as the stepping stone into tumour microenvironment transformation
Magnussen, A. L., & Mills, I. G. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01330-z · Cited by 146
“Integrin adhesion via the β1 chain seems essential for cancer cells to adhere to endothelial cells to both invade and escape from the vascular system through intercalation.(133,104) In the brain, glioblastoma cells with cytoskeletal actin extensions, called flectopodia, adhere to the blood vessels by connecting in an…”
BackgroundBlockade of Tumor-Expressed PD-1 promotes lung cancer growth
Du, S., McCall, N. S., Park, K., Guan, Q., Fontina, P., Ertel, A., Zhan, T., Dicker, A. P., & Lü, B. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1408747 · Cited by 147
Weulersse, M., Asrir, A., Pichler, A., Lemaitre, L., Braun, M., Carrié, N., Joubert, M.-V., Moine, M. L., Souto, L. D., Gaud, G., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.09.006 · Cited by 148
“Despite the existence of several predictive factors such as CD8 T cell infiltration (Tumeh et al., 2014), PD-L1 expression (Larkin et al.”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
