TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts
Open accessAbstract
Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.
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?
Adequate levels of T cell-attracting chemokines such as CXCL9, CXCL10 and CXCL11 are required for migration of T cells into tumours, and TGF-β inhibits the production of these chemoattractants.
“For example, adequate levels of T cell-attracting chemokines such as chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10 and CXCL11 are required for migration of T cells into tumours and TGF-β, a cytokine produced by CAFs and other TME cells and signature molecule of CMS4 tumours, inhibits the production of these chemoattractants.157”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [157]
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
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219 · see citing works
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453 · see citing works
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155 · see citing works
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 · see citing works
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 · see citing works
Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy
Sharma, P., Hu-Lieskovan, S., Wargo, J. A., & Ribas, A. (2017) · Cell · doi:10.1016/j.cell.2017.01.017 · Cited by 5,588 · see citing works
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel III, E. E., Koeppen, H., Astarita, J. L., Cubas, R., et al. (2018) · Nature · doi:10.1038/nature25501 · Cited by 5,400 · see citing works
The consensus molecular subtypes of colorectal cancer
Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., Marisa, L., Roepman, P., Nyamundanda, G., Angelino, P., et al. (2015) · Nature Medicine · doi:10.1038/nm.3967 · Cited by 5,170 · see citing works
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma
Patel, A. P., Tirosh, I., Trombetta, J. J., Shalek, A. K., Gillespie, S. M., Wakimoto, H., Cahill, D. P., Nahed, B. V., Curry, W. T., Martuza, R. L., et al. (2014) · Science · doi:10.1126/science.1254257 · Cited by 5,063 · see citing works
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., et al. (2016) · Science · doi:10.1126/science.aad0501 · Cited by 4,944 · see citing works
The future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878 · see citing works
Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632 · see citing works
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.-F., Testori, A., Grob, J.-J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1104621 · Cited by 4,496 · see citing works
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366 · see citing works
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 · see citing works
Tensional homeostasis and the malignant phenotype
Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., Reinhart-King, C. A., Margulies, S. S., Dembo, M., Boettiger, D., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.08.010 · Cited by 3,941 · see citing works
Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., Carey, V. J., Richardson, A. L., & Weinberg, R. A. (2005) · Cell · doi:10.1016/j.cell.2005.02.034 · Cited by 3,759 · see citing works
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
Hugo, W., Zaretsky, J. M., Sun, L., Song, C., Moreno, B. H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.065 · Cited by 3,448 · see citing works
Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., et al. (2009) · Science · doi:10.1126/science.1171362 · Cited by 3,170 · see citing works
Özdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.005 · Cited by 2,681 · see citing works
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590 · see citing works
T cell exclusion, immune privilege, and the tumor microenvironment
Joyce, J. A., & Fearon, D. T. (2015) · Science · doi:10.1126/science.aaa6204 · Cited by 2,494 · see citing works
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
Riaz, N., Havel, J. J., Makarov, V., Desrichard, A., Urba, W. J., Sims, J. S., Hodi, F. S., Martín-Algarra, S., Mandal, R., Sharfman, W. H., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.028 · Cited by 2,401 · see citing works
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
Powles, T. B., Eder, J. P., Fine, G. D., Braiteh, F. S., Loriot, Y., Cruz, C., Joaquim Bellmunt, B., Burris, H. A., Petrylak, D. P., Teng, S.-L. M., et al. (2014) · Nature · doi:10.1038/nature13904 · Cited by 2,383 · see citing works
Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A., Teinor, J. A., Belleau, P., Biffi, G., Lucito, M. S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0094 · Cited by 2,241 · see citing works
Moffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G. H., Hoadley, K. A., Rashid, N. U., Williams, L. A., Eaton, S. C., Chung, A. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3398 · Cited by 2,194 · see citing works
Feig, C., Jones, J. O., Kraman, M., Wells, R. J. B., Deonarine, A., Chan, D. S., Connell, C. M., Roberts, E. W., Zhao, Q., Caballero, O. L., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320318110 · Cited by 2,100 · see citing works
Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma
Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., Dekleva, E. N., Saunders, T., Becerra, C. P., Tattersall, I. W., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.021 · Cited by 2,085 · see citing works
Induction of angiogenesis during the transition from hyperplasia to neoplasia
Folkman, J., Watson, K., Ingber, D., & Hanahan, D. (1989) · Nature · doi:10.1038/339058a0 · Cited by 1,879 · see citing works
TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
Tauriello, D. V. F., Palomo-Ponce, S., Stork, D., Berenguer-Llergo, A., Badia-Ramentol, J., Iglesias, M., Sevillano, M., Ibiza, S., Cañellas, A., Hernando-Momblona, X., et al. (2018) · Nature · doi:10.1038/nature25492 · Cited by 1,851 · see citing works
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.011 · Cited by 1,705 · see citing works
Erez, N., Truitt, M., Olson, P., & Hanahan, D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.041 · Cited by 1,515 · see citing works
Carcinoma-associated fibroblasts stimulate tumor progression of initiated human epithelium
Olumi, A., Grossfeld, G., Hayward, S., Carroll, P., Cunha, G., Hein, P., & Tlsty, T. (2000) · Breast Cancer Research · doi:10.1186/bcr138 · Cited by 1,463 · see citing works
Zhang, F., Wei, K., Slowikowski, K., Fonseka, C. Y., Rao, D. A., Kelly, S., Goodman, S. M., Tabechian, D. A., Hughes, L. B., Salomon-Escoto, K., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0378-1 · Cited by 1,380 · see citing works
Biffi, G., Oni, T. E., Spielman, B., Hao, Y., Elyada, E., Park, Y., Preall, J., & Tuveson, D. A. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0710 · Cited by 1,360 · see citing works
TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance
Thomas, D. A., & Massagué, J. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.10.012 · Cited by 1,355 · see citing works
Su, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., Wang, M., Luo, M., Xing, Y., Chen, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.009 · Cited by 1,230 · see citing works
Self-citationSingle-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma
Tirosh, I., Venteicher, A. S., Hebert, C. M., Escalante, L. E., Patel, A. P., Yizhak, K., Fisher, J. M., Rodman, C., Mount, C., Filbin, M. G., et al. (2016) · Nature · doi:10.1038/nature20123 · Cited by 1,216 · see citing works
Reyfman, P. A., Walter, J. M., Joshi, N., Anekalla, K. R., McQuattie-Pimentel, A. C., Chiu, S., Fernandez, R., Akbarpour, M., Chen, C.-I., Ren, Z., et al. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201712-2410oc · Cited by 1,203 · see citing works
Immunological hallmarks of stromal cells in the tumour microenvironment
Turley, S. J., Cremasco, V., & Astarita, J. L. (2015) · Nature Reviews Immunology · doi:10.1038/nri3902 · Cited by 1,140 · see citing works
Self-citationSalmon, H., Franciszkiewicz, K., Damotte, D., Dieu-Nosjean, M.-C., Validire, P., Trautmann, A., Mami-Chouaib, F., & Donnadieu, E. (2012) · Journal of Clinical Investigation · doi:10.1172/jci45817 · Cited by 1,138 · see citing works
Hallmarks of cancer: Interactions with the tumor stroma
Pietras, K., & Östman, A. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.02.045 · Cited by 1,137 · see citing works
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α
Kraman, M., Bambrough, P. J., Arnold, J. N., Roberts, E. W., Magiera, L., Jones, J. O., Gopinathan, A., Tuveson, D. A., & Fearon, D. T. (2010) · Science · doi:10.1126/science.1195300 · Cited by 1,134 · see citing works
Li, H., Courtois, E. T., Sengupta, D., Tan, Y., Chen, K. H., Goh, J. J. L., Kong, S. L., Chua, C., Hon, L. K., Tan, W. S., et al. (2017) · Nature Genetics · doi:10.1038/ng.3818 · Cited by 1,080 · see citing works
Stromal gene expression defines poor-prognosis subtypes in colorectal cancer
Calon, A., Lonardo, E., Berenguer-Llergo, A., Espinet, E., Hernando-Momblona, X., Iglesias, M., Sevillano, M., Palomo-Ponce, S., Tauriello, D. V. F., Byrom, D., et al. (2015) · Nature Genetics · doi:10.1038/ng.3225 · Cited by 1,070 · see citing works
Acerbi, I., Cassereau, L., Dean, I. S., Shi, Q., Au, A., Park, C., Chen, Y. Y., Liphardt, J., Hwang, E. S., & Weaver, V. M. (2015) · Integrative Biology · doi:10.1039/c5ib00040h · Cited by 1,062 · see citing works
Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D. V. F., Iglesias, M., Céspedes, M. V., Sevillano, M., Nadal, C., Jung, P., Zhang, X. H.-F., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.013 · Cited by 1,060 · see citing works
Distinct fibroblast subsets drive inflammation and damage in arthritis
Croft, A. P., Campos, J., Jansen, K., Turner, J. D., Marshall, J., Attar, M., Savary, L., Wehmeyer, C., Naylor, A. J., Kemble, S., et al. (2019) · Nature · doi:10.1038/s41586-019-1263-7 · Cited by 976 · see citing works
Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis
Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G. H., & Hanahan, D. (1999) · Genes & Development · doi:10.1101/gad.13.11.1382 · Cited by 946 · see citing works
Dominguez, C. X., Müller, S., Keerthivasan, S., Koeppen, H., Hung, J., Gierke, S., Breart, B., Foreman, O., Bainbridge, T. W., Castiglioni, A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0644 · Cited by 857 · see citing works
Kojima, Y., Acar, A., Eaton, E. N., Mellody, K. T., Scheel, C., Ben‐Porath, I., Önder, T. T., Wang, Z. C., Richardson, A. L., Weinberg, R. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013805107 · Cited by 851 · see citing works
Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer
Ma, L., Hernandez, M. O., Zhao, Y., Mehta, M., Tran, B. Q., Kelly, M. C., Rae, Z., Hernandez, J. M., Davis, J. L., Martin, S. P., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.08.007 · Cited by 844 · see citing works
Boire, A. A., Covic, L., Agarwal, A., Jacques, S. L., Sherifi, S., & Kuliopulos, A. (2005) · Cell · doi:10.1016/j.cell.2004.12.018 · Cited by 841 · see citing works
De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent
de Visser, K. E., Korets, L. V., & Coussens, L. M. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.014 · Cited by 826 · see citing works
Bartoschek, M., Oskolkov, N., Bocci, M., Lövrot, J., Larsson, C., Sommarin, M., Madsen, C. D., Lindgren, D., Pekar, G., Karlsson, G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07582-3 · Cited by 826 · see citing works
Chaudhuri, O., Koshy, S. T., Branco da Cunha, C., Shin, J.-W., Verbeke, C. S., Allison, K. H., & Mooney, D. J. (2014) · Nature Materials · doi:10.1038/nmat4009 · Cited by 820 · see citing works
TGF- β signaling in cancer – a double-edged sword
Akhurst, R. J., & Derynck, R. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02130-4 · Cited by 756 · see citing works
Identification of fibroblast heterogeneity in the tumor microenvironment
Sugimoto, H., Mundel, T. M., Kieran, M. W., & Kalluri, R. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.12.3354 · Cited by 700 · see citing works
Yang, J. C., Hughes, M., Kammula, U., Royal, R., Sherry, R. M., Topalian, S. L., Suri, K. B., Levy, C., Allen, T., Mavroukakis, S., et al. (2007) · Journal of Immunotherapy · doi:10.1097/cji.0b013e318156e47e · Cited by 697 · see citing works
Identification and isolation of a dermal lineage with intrinsic fibrogenic potential
Rinkevich, Y., Walmsley, G. G., Hu, M. S.-M., Maan, Z. N., Newman, A. M., Drukker, M., Januszyk, M., Krampitz, G. W., Gurtner, G. C., Lorenz, H. P., et al. (2015) · Science · doi:10.1126/science.aaa2151 · Cited by 695 · see citing works
CANCER-ASSOCIATED FIBROBLAST EXOSOMES REGULATE SURVIVAL AND PROLIFERATION OF PANCREATIC CANCER CELLS
Richards, K. E., Zeleniak, A. E., Fishel, M., Wu, J.-M., Littlepage, L. E., & Hill, R. (2016) · Oncogene · doi:10.1038/onc.2016.353 · Cited by 656 · see citing works
Self-citationCo-evolution of tumor cells and their microenvironment
Polyák, K., Haviv, I., & Campbell, I. (2008) · Trends in Genetics · doi:10.1016/j.tig.2008.10.012 · Cited by 622 · see citing works
Powles, T. B., Kockx, M. M., Rodríguez‐Vida, A., Durán, I., Crabb, S. J., van der Heijden, M. S., Szabados, B. E., Pous, A. F., Gravis, G., Anido, U., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0628-7 · Cited by 592 · see citing works
Ene–Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C., Marshall, J. F., Chin–Aleong, J., Chelala, C., Gribben, J. G., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.07.025 · Cited by 579 · see citing works
Samuel, M. S., Lopez, J. I., McGhee, E. J., Croft, D. R., Strachan, D., Timpson, P., Munro, J., Schröder, E., Zhou, J., Brunton, V. G., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.05.008 · Cited by 542 · see citing works
Self-citationStromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer
Ligorio, M., Sil, S., Malagon-Lopez, J., Nieman, L. T., Misale, S., Pilato, M. D., Ebright, R. Y., Karabacak, M., Kulkarni, A. S., Liu, A., et al. (2018) · Cell · doi:10.1016/j.cell.2019.05.012 · Cited by 534 · see citing works
Single-Cell Deconvolution of Fibroblast Heterogeneity in Mouse Pulmonary Fibrosis
Xie, T., Wang, Y., Deng, N., Huang, G., Taghavifar, F., Geng, Y., Liu, N., Kulur, V., Yao, C., Chen, P., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.010 · Cited by 528 · see citing works
Ting, D. T., Wittner, B. S., Ligorio, M., Jordan, N. V., Shah, A. M., Miyamoto, D. T., Aceto, N., Bersani, F., Brannigan, B. W., Xega, K., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.029 · Cited by 521 · see citing works
Rønnov‐Jessen, L., & PETERSEN, O. W. (1993) · PubMed · Cited by 514 · see citing works
Fibroblast heterogeneity: implications for human disease
Lynch, M. D., & Watt, F. M. (2018) · Journal of Clinical Investigation · doi:10.1172/jci93555 · Cited by 490 · see citing works
Nakasone, E. S., Askautrud, H. A., Kees, T., Park, J.-H., Plaks, V., Ewald, A. J., Fein, M. R., Rasch, M. G., Tan, Y.-X., Qiu, J., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.017 · Cited by 477 · see citing works
Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity
Rodda, L. B., Lu, E., Bennett, M. L., Sokol, C. L., Wang, X., Luther, S. A., Barres, B. A., Luster, A. D., Ye, C., & Cyster, J. G. (2018) · Immunity · doi:10.1016/j.immuni.2018.04.006 · Cited by 441 · see citing works
Cazet, A. S., Hui, M. N., Elsworth, B. L., Wu, S. Z., Roden, D., Chan, C.-L., Skhinas, J. N., Collot, R., Yang, J., Harvey, K., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05220-6 · Cited by 437 · see citing works
Bernard, V., Semaan, A., Huang, J. H., Lucas, F. A. S., Mulu, F. C., Stephens, B. M., Guerrero, P. A., Huang, Y., Zhao, J., Kamyabi, N., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1955 · Cited by 387 · see citing works
Wu, X., Pan, T., Zhou, Q., Li, J., Yu, Z., Wang, X., Li, J., Li, C., Yan, M., Zhu, Z., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15119 · Cited by 367 · see citing works
Clinical Implications of Fibroblast Activation Protein in Patients with Colon Cancer
Henry, L. R., Lee, H., Lee, J. S., Klein–Szanto, A. J., Watts, P., Ross, E. A., Chen, W., & Cheng, J. D. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1746 · Cited by 365 · see citing works
van den Eertwegh, A. J. M., Versluis, J., van den Berg, H. P., Santegoets, S. J. A. M., van Moorselaar, R. J. A., van der Sluis, T. M., Gall, H. E., Harding, T. C., Jooss, K. U., Lowy, I., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70007-4 · Cited by 355 · see citing works
Stromal Myofibroblasts Predict Disease Recurrence for Colorectal Cancer
辻野, 督., Seshimo, I., Yamamoto, H., Ngan, C. Y., Ezumi, K., Takemasa, I., Ikeda, M., Sekimoto, M., Matsuura∥, N., & Monden, M. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2191 · Cited by 352 · see citing works
Neuzillet, C., Tijeras‐Raballand, A., Ragulan, C., Cros, J. F., Patil, Y., Martinet, M., Erkan, M., Kleeff, J. H., Wilson, J. S., Apte, M. V., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5224 · Cited by 296 · see citing works
Shekhar, M. P. V., Werdell, J., Santner, S. J., Pauley, R. J., & Tait, L. R. (2001) · PubMed · Cited by 286 · see citing works
Systemic and local immunosuppression in pancreatic cancer patients.
von Bernstorff, W., Voss, M., Freichel, S., Schmid, A., Vogel, I., Jöhnk, C., Henne‐Bruns, D., Kremer, B., & Kalthoff, H. (2001) · PubMed · Cited by 279 · see citing works
Lewis, M. P., Lygoe, K. A., Nystrom, M. L., Anderson, W., Speight, P. M., Marshall, J. F., & Thomas, G. J. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6601611 · Cited by 262 · see citing works
Tuxhorn, J. A., McAlhany, S. J., Dang, T. D., Ayala, G. E., & Rowley, D. R. (2002) · PubMed · Cited by 261 · see citing works
Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer
Hartmann, N., Giese, N. A., Giese, T., Poschke, I. C., Offringa, R., Werner, J. M., & Ryschich, E. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2972 · Cited by 231 · see citing works
Tumorigenic conversion of immortal human keratinocytes through stromal cell activation
Skobe, M., & Fusenig, N. E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.3.1050 · Cited by 231 · see citing works
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 · see citing works
Cremasco, V., Astarita, J. L., Grauel, A. L., Keerthivasan, S., MacIsaac, K. D., Woodruff, M. C., Wu, M. P., Spel, L., Santoro, S. P., Amoozgar, Z., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0098 · Cited by 208 · see citing works
Self-citationImmunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology
Nayar, S., Campos, J., Smith, C. G., Iannizzotto, V., Gardner, D. H., Mourcin, F., Roulois, D., Turner, J., Sylvestre, M., Asam, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1905301116 · Cited by 203 · see citing works
Heßmann, E., Patzak, M. S., Klein, L., Chen, N., Kari, V., Ramu, I., Bapiro, T. E., Frese, K. K., Gopinathan, A., Richards, F. M., et al. (2017) · Gut · doi:10.1136/gutjnl-2016-311954 · Cited by 202 · see citing works
Self-citationCD10+ Pancreatic Stellate Cells Enhance the Progression of Pancreatic Cancer
Ikenaga, N., Ohuchida, K., Mizumoto, K., et al. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.05.084 · Cited by 186 · see citing works
TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer
Principe, D. R., Park, A. J., Dorman, M. J., Kumar, S., Viswakarma, N., Rubin, J., Torres, C., McKinney, R. D., Munshi, H. G., Grippo, P. J., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0850 · Cited by 126 · see citing works
Berdiel‐Acer, M., Pamplona, R. S., Calon, A., Cuadras, D., Berenguer, A., Sanjuán, X., Paúles, M. J., Salazar, R., Moreno, V. R., Batlle, E., et al. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.04.006 · Cited by 112 · see citing works
ST Pipeline: an automated pipeline for spatial mapping of unique transcripts
Navarro, J. F., Sjöstrand, J., Salmén, F., Lundeberg, J., & Ståhl, P. L. (2017) · Bioinformatics · doi:10.1093/bioinformatics/btx211 · Cited by 103 · see citing works
Cheng, H., Onder, L., Cupovic, J., Boesch, M., Novković, M., Pikor, N. B., Tarantino, I., Rodriguez, R., Schneider, T., Jochum, W., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.12.998 · Cited by 88 · see citing works
Fibroblasts as a source of self-antigens for central immune tolerance
Nitta, T., Tsutsumi, M., Nitta, S., Muro, R., Suzuki, E. C., Nakano, K., Tomofuji, Y., Sawa, S., Okamura, T., Penninger, J. M., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0756-8 · Cited by 84 · see citing works
Stromal aspects of breast carcinoma
Tremblay, G. (1979) · Experimental and Molecular Pathology · doi:10.1016/0014-4800(79)90026-1 · Cited by 78 · see citing works
Paland, N., Kamer, I., Kogan-Sakin, I., Madar, S., Goldfinger, N., & Rotter, V. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-09-0073 · Cited by 70 · see citing works
The prognostic significance of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma
Park, H., Lee, Y., Lee, H., Kim, J.-W., Hwang, J., Kim, J., Yoon, Y., Han, H., & Kim, H. (2017) · Tumor Biology · doi:10.1177/1010428317718403 · Cited by 62 · see citing works
Mezawa, Y., Daigo, Y., Takano, A., Miyagi, Y., Yokose, T., Yamashita, T., Morimoto, C., Hino, O., & Orimo, A. (2019) · Cancer Medicine · doi:10.1002/cam4.2249 · Cited by 55 · see citing works
Expression of cyclin D2 and D3 in lymphoid lesions
Teramoto, N., Tamm, K. P., Székely, L., Polack, A., Yoshino, T., Akagi, T., & Klein, G. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19990517)81:4 · Cited by 42 · see citing works
Bedinger, D., Lao, L., Khan, S., Lee, S., Takeuchi, T., & Mirza, A. M. (2016) · mAbs · doi:10.1080/19420862.2015.1115166 · Cited by 42 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Exploring tissue architecture using spatial transcriptomics
Rao, A., Barkley, D., França, G. S., & Yanai, I. (2021) · Nature · doi:10.1038/s41586-021-03634-9 · Cited by 1,700 · see citing works
From bulk, single-cell to spatial RNA sequencing
Li, X., & Wang, C.-Y. (2021) · International Journal of Oral Science · doi:10.1038/s41368-021-00146-0 · Cited by 605 · see citing works
Overcoming TGFβ-mediated immune evasion in cancer
Tauriello, D. V. F., Sancho, E., & Batlle, E. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00413-6 · Cited by 377 · see citing works
Tumor cell plasticity in targeted therapy-induced resistance: Mechanisms and new strategies
Shi, Z.-D., Pang, K., Wu, Z.-X., Dong, Y., Hao, L., Qin, J.-X., Wang, W., Chen, Z.-S., & Han, C.-H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01383-x · Cited by 256 · see citing works
Current and emerging concepts for systemic treatment of metastatic colorectal cancer
Steup, C., Kennel, K. B., Neurath, M. F., Fichtner-Feigl, S., & Greten, F. R. (2025) · Gut · doi:10.1136/gutjnl-2025-335412 · Cited by 39 · see citing works
- Authors
- Grauel, A. L., Nguyen, B., Ruddy, D., Laszewski, T., Schwartz, S., Chang, J., Chen, J., Piquet, M., Pelletier, M., Yan, Z., Kirkpatrick, N. D., Wu, J., deWeck, A., Riester, M., Hims, M., Geyer, F. C., Wagner, J., MacIsaac, K., Deeds, J., Diwanji, R., Jayaraman, P., Yu, Y., Simmons, Q., Weng, S., Raza, A., Minie, B., Dostalek, M., Chikkegowda, P., Ruda, V., Iartchouk, O., Chen, N., Thierry, R., Zhou, J., Pruteanu-Malinici, I., Fabre, C., Engelman, J. A., Dranoff, G., & Cremasco, V.
- Corresponding author
- Cremasco, Viviana
- ORCID
- Grauel, Angelo L.
- Nguyen, Beverly
- Ruddy, David
- Laszewski, Tyler
- Chang, Jonathan
- Chen, Julie
- Piquet, Michelle
- Pelletier, Marc
- Wu, Jincheng
- Riester, Markus
- Geyer, Felipe Correa
- Wagner, Joel
- Diwanji, Rohan
- Weng, Shaobu
- Raza, Alina
- Minie, Brian
- Ruda, Vera
- Iartchouk, Oleg
- Chen, Naiyan
- Zhou, Joseph
- Pruteanu-Malinici, Iulian
- Fabre, Claire
- Engelman, Jeffrey A.
- Dranoff, Glenn
- Cremasco, Viviana
- Venue
- Nature Communications
- Published
- 2020-12-09
- Volume
- 11
- Issue
- 1
- Pages
- 6315-6315
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7725805
- OpenAlex
- W3112223966
- Cited by
- 211
- References
- 101
- Citations by year
- 2026: 34 · 2025: 31 · 2024: 33 · 2023: 36 · 2022: 56 · 2021: 21
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- TGF-beta blockade, cancer-associated fibroblasts, tumor stroma, myofibroblasts, tumor microenvironment, antitumor immunity, anti-PD-1 therapy, fibroblast heterogeneity
- MeSH terms
- Cell Plasticity, Cancer-Associated Fibroblasts, Immune Checkpoint Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Disease Models, Animal, Drug Synergism, Female, Humans, Transforming Growth Factor beta, Interferon-beta, Stromal Cells, Cell Line, Tumor, Mice, Tumor Microenvironment, 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
