Tumor-Associated Macrophages and Survival in Classic Hodgkin's Lymphoma
Open accessAbstract
BACKGROUND: Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. METHODS: Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. RESULTS: Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies. CONCLUSIONS: An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.
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
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?
TAM presence and number directly correlate with prognosis in several cancer types and model systems.
“Indeed, TAM presence and number has been directly correlated with prognosis in a number of cancer types and model systems [42–44].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [43]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Breiman, L. (2001) · Machine Learning · doi:10.1023/a:1010933404324 · Cited by 133,538 · see citing works
MANTOVANI, A., SOZZANI, S., LOCATI, M., ALLAVENA, P., & SICA, A. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02302-5 · Cited by 5,528 · see citing works
A gene atlas of the mouse and human protein-encoding transcriptomes
Su, A. I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K. A., Block, D., Zhang, J., Soden, R., Hayakawa, M., Kreiman, G., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400782101 · Cited by 3,475 · see citing works
Stromal Gene Signatures in Large-B-Cell Lymphomas
Lenz, G., Wright, G. W., Davé, S. S., Xiao, W., Powell, J. I., Zhao, H., Xu, W., Tan, B. T., Goldschmidt, N., Iqbal, J., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802885 · Cited by 1,818 · see citing works
Self-citationA Prognostic Score for Advanced Hodgkin's Disease
Hasenclever, D., Diehl, V., Armitage, J. O., Assouline, D., Björkholm, M., Brusamolino, E., Canellos, G. P., Carde, P. P., Crowther, D., Cunningham, D., et al. (1998) · New England Journal of Medicine · doi:10.1056/nejm199811193392104 · Cited by 1,734 · see citing works
Davé, S. S., Wright, G. W., Tan, B. K., Rosenwald, A., Gascoyne, R. D., Chan, W. C., Fisher, R. I., Braziel, R. M., Rimsza, L. M., Grogan, T. M., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa041869 · Cited by 1,417 · see citing works
Self-citationChemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD
Canellos, G. P., Anderson, J. R., PROPERT, K. J., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199211193272102 · Cited by 1,162 · see citing works
Molecular Diagnosis of Burkitt's Lymphoma
Davé, S. S., Fu, K., Wright, G. W., Lam, L. T., Kluin, P. M., Boerma, E.-J. G., Greiner, T. C., Weisenburger, D. D., Rosenwald, A., Ott, G., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa055759 · Cited by 897 · see citing works
Self-citationSparse multinomial logistic regression: fast algorithms and generalization bounds
Krishnapuram, B., Carin, L., Figueiredo, M. A. T., & Hartemink, A. J. (2005) · IEEE Transactions on Pattern Analysis and Machine Intelligence · doi:10.1109/tpami.2005.127 · Cited by 872 · see citing works
The biology of Hodgkin's lymphoma
Küppers, R. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2542 · Cited by 694 · see citing works
Farinha, P., Masoudi, H., Skinnider, B., Shumansky, K., Spinelli, J. J., Gill, K. K., Klasa, R. J., Voss, N., Connors, J. M., & Gascoyne, R. D. (2005) · Blood · doi:10.1182/blood-2005-04-1565 · Cited by 460 · see citing works
Self-citationÁlvaro, T., Lejeune, M., Salvadó, M. T., Bosch, R., García, J. F., Jaén, J., Banham, A. H., Roncador, G., Montalbán, C., & Piris, M. A. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1869 · Cited by 449 · see citing works
Tzankov, A., Meier, C., Hirschmann, P., Went, P., Pileri, S. A., & Dirnhofer, S. (2008) · Haematologica · doi:10.3324/haematol.11702 · Cited by 412 · see citing works
Chetaille, B., Bertucci, F., Finetti, P., Esterni, B., Stamatoullas, A., Picquenot, J. M., Copin, M. C., Morschhauser, F., Casasnovas, O., Petrella, T., et al. (2008) · Blood · doi:10.1182/blood-2008-07-168096 · Cited by 251 · see citing works
A library of gene expression signatures to illuminate normal and pathological lymphoid biology
Shaffer, A. L., Wright, G. W., Yang, L., Powell, J. I., Ngo, V. N., Lamy, L., Lam, L. T., Davis, R. E., & Staudt, L. M. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00373.x · Cited by 228 · see citing works
Self-citationCirculating clonotypic B cells in classic Hodgkin lymphoma
Jones, R. J., Gocke, C. D., Kasamon, Y. L., et al. (2009) · Blood · doi:10.1182/blood-2008-11-189688 · Cited by 171 · see citing works
Hodgkin’s Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease
Diehl, V., Stein, H., Hummel, M., Zollinger, R., & Connors, J. M. (2003) · Hematology · doi:10.1182/asheducation-2003.1.225 · Cited by 169 · see citing works
Self-citationA pilot study of rituximab in patients with recurrent, classic Hodgkin disease
Younes, A., Romaguera, J. E., Hagemeister, F. B., et al. (2003) · Cancer · doi:10.1002/cncr.11511 · Cited by 168 · see citing works
Sánchez‐Aguilera, A. (2006) · Blood · doi:10.1182/blood-2005-12-5125 · Cited by 142 · see citing works
Diepstra, A., Imhoff, G. W. V., Karim‐Kos, H. E., van den Berg, A., Meerman, G. J. T., Niens, M., Nolte, I. M., Bastiaannet, E., Schaapveld, M., Vellenga, E., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.10.0917 · Cited by 131 · see citing works
Gene Expression Profiling in Human Preadipocytes and Adipocytes by Microarray Analysis
Urs, S., Smith, C. J., Campbell, B., Saxton, A. M., Taylor, J. W., Zhang, B., Snoddy, J. R., Voy, B. H., & Moustaïd‐Moussa, N. (2004) · Journal of Nutrition · doi:10.1093/jn/134.4.762 · Cited by 129 · see citing works
Natkunam, Y. (2005) · Blood · doi:10.1182/blood-2004-08-3112 · Cited by 117 · see citing works
Kelley, T. W., Pohlman, B. L., Elson, P. J., & Hsi, E. D. (2007) · American Journal of Clinical Pathology · doi:10.1309/nb3947k383dj0lq2 · Cited by 116 · see citing works
Álvaro-Naranjo, T., Lejeune, M., Salvadó-Usach, T., et al. (2005) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190500220654 · Cited by 99 · see citing works
Gene expression profiling defines molecular subtypes of classical Hodgkin's disease
Devilard, É., Bertucci, F., Trempat, P., Bouabdallah, R., Loriod, B., Giaconia, A., Brousset, P., Granjeaud, S., Nguyen, C., Birnbaum, D., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205418 · Cited by 96 · see citing works
Expression of bcl-2 in Classical Hodgkin's Lymphoma: An Independent Predictor of Poor Outcome
Sup, S. J., Alemany, C. A., Pohlman, B. L., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.358 · Cited by 68 · see citing works
Analysis of Gene Expression in the Tumor-Associated Macrophage
Duff, M. D., MESTRE, J. R., Maddali, S., Yan, Z., Stapleton, P. P., & Daly, J. M. (2007) · Journal of Surgical Research · doi:10.1016/j.jss.2006.12.542 · Cited by 48 · see citing works
Perz, J. B., Giles, C. M., Szydlo, R., et al. (2006) · Bone Marrow Transplantation · doi:10.1038/sj.bmt.1705544 · Cited by 28 · see citing works
Topoisomerase IIα Expression as an Independent Prognostic Factor in Hodgkin's Lymphoma
Doussis-Anagnostopoulou, I. A., Vassilakopoulos, T. P., Thymara, I., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1395 · Cited by 25 · see citing works
Karube, K., Ohshima, K., Suzumiya, J., Kawano, R., Kikuchi, M., & Harada, M. (2005) · Annals of Oncology · doi:10.1093/annonc/mdj064 · Cited by 19 · see citing works
Falchi, L., Capello, D., Palumbo, B., et al. (2007) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2007.00952.x · Cited by 18 · see citing works
Odaka, C., & Izumiyama, S. (2005) · Cellular Immunology · doi:10.1016/j.cellimm.2005.06.011 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [1]Björkholm M Axdorph U Grimfors G Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin's disease: a prospective randomized trial Ann Oncol 1995 6 895 9 8624292
Cited by
Sorted by citations
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335 · see citing works
Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · see citing works
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840 · see citing works
DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., Gallagher, W. M., Wadhwani, N., Keil, S. D., Junaid, S. A., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8274.cd-10-0028 · Cited by 1,715 · see citing works
The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy
Bruni, D., Angell, H. K., & Galon, J. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0285-7 · Cited by 1,586 · see citing works
Rodell, C. B., Arlauckas, S. P., Cuccarese, M. F., Garris, C. S., Li, R., Ahmed, M. S., Kohler, R. H., Pittet, M. J., & Weissleder, R. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0236-8 · Cited by 1,099 · see citing works
Macrophage Regulation of Tumor Responses to Anticancer Therapies
De Palma, M., & Lewis, C. E. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.013 · Cited by 1,079 · see citing works
Macrophages in Tumor Microenvironments and the Progression of Tumors
Hao, N.-B., Lü, M.-H., Fan, Y.-H., Cao, Y.-L., Zhang, Z.-R., & Yang, S.-M. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/948098 · Cited by 1,003 · see citing works
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., & Badylak, S. F. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.02.034 · Cited by 926 · see citing works
Therapeutic siRNA silencing in inflammatory monocytes in mice
Leuschner, F., Dutta, P., Gorbatov, R., Novobrantseva, T. I., Donahoe, J. S., Courties, G., Lee, K. M., Kim, J. I., Markmann, J. F., Marinelli, B., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1989 · Cited by 839 · see citing works
The role of myeloid cells in cancer therapies
Engblom, C., Pfirschke, C., & Pittet, M. J. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.54 · Cited by 788 · see citing works
Imaging macrophages with nanoparticles
Weissleder, R., Nahrendorf, M., & Pittet, M. J. (2014) · Nature Materials · doi:10.1038/nmat3780 · Cited by 809 · see citing works
Macrophage polarization in pathology
Sica, A., Erreni, M., Allavena, P., & Porta, C. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1995-y · Cited by 673 · see citing works
Regulation of macrophage development and function in peripheral tissues
Lavin, Y., Mortha, A., Rahman, A., & Merad, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3920 · Cited by 680 · see citing works
Tumor-associated macrophages: Functional diversity, clinical significance, and open questions
Biswas, S. K., Allavena, P., & Mantovani, A. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0367-7 · Cited by 551 · see citing works
Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders?
Parisi, L., Gini, E., Baci, D., Tremolati, M., Fanuli, M., Bassani, B., Farronato, G., Bruno, A., & Mortara, L. (2018) · Journal of Immunology Research · doi:10.1155/2018/8917804 · Cited by 508 · see citing works
Tumour‐associated macrophages act as a slow‐release reservoir of nano‐therapeutic Pt(IV) pro‐drug
Miller, M. A., Zheng, Y.-R., Gadde, S., Pfirschke, C., Zope, H., Engblom, C., Kohler, R. H., Iwamoto, Y., Yang, K. S., Askevold, B., et al. (2015) · Nature Communications · doi:10.1038/ncomms9692 · Cited by 441 · see citing works
T cell–induced CSF1 promotes melanoma resistance to PD1 blockade
Neubert, N. J., Schmittnaegel, M., Bordry, N., Nassiri, S., Wald, N., Martignier, C., Tillé, L., Homicsko, K., Damsky, W., Maby-El Hajjami, H., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan3311 · Cited by 308 · see citing works
Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer
Tang, X. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.01.024 · Cited by 276 · see citing works
A role of PIEZO1 in iron metabolism in mice and humans
Ma, S., Dubin, A. E., Zhang, Y., Mousavi, S. A. R., Wang, Y., Coombs, A. M., Loud, M., Andolfo, I., & Patapoutian, A. (2021) · Cell · doi:10.1016/j.cell.2021.01.024 · Cited by 232 · see citing works
Martinez-Outschoorn, U. E., Pestell, R. G., Howell, A., Tykocinski, M. L., Nagajyothi, F., Machado, F. S., Tanowitz, H. B., Sotgia, F., & Lisanti, M. P. (2011) · Cell Cycle · doi:10.4161/cc.10.24.18487 · Cited by 157 · see citing works
Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer
Luo, Q., Zheng, N., Jiang, L., Wang, T., Zhang, P., Liu, Y., Zheng, P., Wang, W., Xie, G., Chen, L., et al. (2020) · Cancer Science · doi:10.1111/cas.14616 · Cited by 126 · see citing works
Yan, Z.-X., Li, L., Wang, W., OuYang, B.-S., Cheng, S., Wang, L., Wu, W., Xu, P.-P., Muftuoglu, M., Hao, M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0101 · Cited by 115 · see citing works
Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer
Lu, W., Yu, W., He, J., Liu, W., Yang, J., Lin, X., Zhang, Y., Wang, X., Jiang, W., Luo, J., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202012798 · Cited by 112 · see citing works
TGF-beta: a master switch in tumor immunity
Gigante, M., Gesualdo, L., & Ranieri, E. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212802430378 · Cited by 45 · see citing works
- Authors
- Steidl, C., Lee, T., Shah, S. P., Farinha, P., Han, G., Nayar, T., Delaney, A., Jones, S. J., Iqbal, J., Weisenburger, D. D., Bast, M. A., Rosenwald, A., Muller-Hermelink, H.-K., Rimsza, L. M., Campo, E., Delabie, J., Braziel, R. M., Cook, J. R., Tubbs, R. R., Jaffe, E. S., Lenz, G., Connors, J. M., Staudt, L. M., Chan, W. C., & Gascoyne, R. D.
- Affiliations
- BC Cancer Agency (CA)
- University of British Columbia (CA)
- Cleveland Clinic (US)
- National Institutes of Health (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2010-03-11
- Volume
- 362
- Issue
- 10
- Pages
- 875-885
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2897174
- OpenAlex
- W2034400622
- Cited by
- 1,262
- References
- 32
- Citations by year
- 2026: 19 · 2025: 34 · 2024: 39 · 2023: 64 · 2022: 66 · 2021: 84 · 2020: 78 · 2019: 67 · 2018: 87 · 2017: 85 · 2016: 81 · 2015: 107 · 2014: 86 · 2013: 115 · 2012: 103
- FWCI
- 79.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u01ca114778-05)
- Canadian Institutes of Health Research (178536)
- National Cancer Institute (U01-CA-114778, U01-CA114778-01)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- tumor-associated macrophages, CD68, prognostic factors, progression-free survival, disease-specific survival, International Prognostic Score, gene expression signatures, risk stratification
- MeSH terms
- CD68 Molecule, Adolescent, Adult, Aged, Aged, 80 and over, Analysis of Variance, Child, Female, Hodgkin Disease, Humans, Immunohistochemistry, Lymph Nodes, Macrophages, Male, Middle Aged, Neoplasm Staging, Prognosis, RNA, Neoplasm, Biomarkers, Tumor, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Gene Expression, Gene Expression Regulation, Neoplastic, Survival Rate, Reed-Sternberg Cells, Treatment Failure, Disease-Free Survival, Gene Expression Profiling, Kaplan-Meier Estimate, Young Adult
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
