The DOI matches its Crossref record; 105 of the 105 references it cites were found in a registry or an index.
Reversing T-cell Dysfunction and Exhaustion in Cancer
Open accessAbstract
In the context of chronic antigen exposure in chronic viral infections and cancer, T cells become exhausted/dysfunctional. These exhausted T cells exhibit defective proliferative capacities and cytokine production, but are not totally inert and may exert lytic functions. Importantly, exhausted T cells upregulate multiple inhibitory receptors/immune checkpoints that bind to their ligands expressed by tumor cells and antigen-presenting cells in the tumor microenvironment (TME). Immune checkpoint blockades with anti-CTL antigen 4 (CTLA-4) and/or anti-programmed death 1 (PD-1) mAbs successfully reinvigorate tumor-infiltrating T lymphocytes and provide persistent clinical benefits to a large number of patients with advanced cancer. This great and long-awaited success for the immunotherapy of cancer has infused considerable enthusiasm in the field of oncology and fostered the development of combinatorial strategies to target the multiple mechanisms of tumor-induced T-cell dysfunction. Here, we review the critical immunoregulatory mechanisms driving T-cell exhaustion in the TME. We also discuss the development of promising combinatorial immunotherapies to counteract the mechanisms of tumor-induced T-cell dysfunction to improve the clinical efficacy of current immune checkpoint blockades. As our understanding of the mechanisms supporting tumor-induced T-cell dysfunction improves based upon preclinical and clinical studies, we expect that novel combinatorial immunotherapies will emerge to improve the clinical outcome of patients with advanced cancers. Clin Cancer Res; 22(8); 1856–64. ©2016 AACR. See all articles in this CCR Focus section, “Opportunities and Challenges in Cancer Immunotherapy.”
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?
In the citing paper
“the gut microbiome is a major tumor-extrinsic regulator of responses to anti–PD-1 (6–9).”
From Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients (2021) · cites this paper as [9]
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
1 retracted
TIGIT predominantly regulates the immune response via regulatory T cells
Kurtuluş, S., Sakuishi, K., Ngiow, S. F., Joller, N., Tan, D. J., Teng, M. W. L., Smyth, M. J., Kuchroo, V. K., & Anderson, A. C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81187 · Cited by 558
RetractedPD-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
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
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., et al. (2015) · Science · doi:10.1126/science.aaa1348 · Cited by 7,802
Interleukin-10 and the Interleukin-10 Receptor
Moore, K. W., de Waal Malefyt, R., Coffman, R. L., & O'Garra, A. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.683 · Cited by 6,737
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
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652
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
Research works printed but not linked: 1
- Gangadhar, 2015, Preliminary results from a phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers [abstract], Abstract nr O7
Cited by
Sorted by citations
Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients
Davar, D., Dzutsev, A. K., McCulloch, J. A., Rodrigues, R. R., Chauvin, J.-M., Morrison, R. M., Deblasio, R. N., Menna, C., Ding, Q., Pagliano, O., et al. (2021) · Science · doi:10.1126/science.abf3363 · Cited by 1,781
Self-citationImmunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?
Fulop, T., Larbi, A., Dupuis, G., Le Page, A., Frost, E. H., Cohen, A. A., Witkowski, J. M., & Franceschi, C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01960 · Cited by 1,364
T Cell Dysfunction and Exhaustion in Cancer
Zhang, Z., Liu, S., Zhang, B., Qiao, L., Zhang, Y., & Zhang, Y. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00017 · Cited by 385
“Thus, a combined treatment of IL-10 or TGF-β inhibitor(s) with ICB represents a promising strategy for immunotherapy strategy (Zarour, 2016).”
BackgroundMethodMarkers of T Cell Senescence in Humans
Xu, W., & Larbi, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081742 · Cited by 261
Immunological Mechanisms Underneath the Efficacy of Cancer Therapy
Galluzzi, L., Zitvogel, L., & Kroemer, G. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-16-0197 · Cited by 175
Metadata
- Authors
- Zarour, H. M.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Zarour, Hassane M.
- ORCID
- Zarour, Hassane M.
- Venue
- Clinical Cancer Research
- Published
- 2016-04-14
- Volume
- 22
- Issue
- 8
- Pages
- 1856-1864
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4872712
- OpenAlex
- W2336635113
- Cited by
- 462
- References
- 105
- Citations by year
- 2026: 29 · 2025: 42 · 2024: 35 · 2023: 55 · 2022: 59 · 2021: 64 · 2020: 53 · 2019: 46 · 2018: 38 · 2017: 25 · 2016: 15
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH Melanoma Research Alliance, and a Clinical Strategy Team Grant from the Cancer Research Institute (R01CA157467 and P50CA121973)
- 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
- T cell exhaustion, T cell dysfunction, tumor microenvironment, immune checkpoint, CTLA-4, PD-1, immune checkpoint blockade, cancer immunotherapy, combination immunotherapy, inhibitory receptors, chronic viral infection, tumor-infiltrating T cells
- MeSH terms
- Animals, Antibodies, Monoclonal, Antigen-Presenting Cells, Antineoplastic Agents, Gene Expression Regulation, Humans, Immunologic Factors, Neoplasms, T-Lymphocytes, Signal Transduction, Cytokines, Myeloid Cells, Epigenesis, Genetic, Immunomodulation, Molecular Targeted Therapy, Tumor Microenvironment, CTLA-4 Antigen, Costimulatory and Inhibitory T-Cell Receptors, 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
