Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells
Open accessAbstract
Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and “normal” stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8 + T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation.
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Antigen cross presentation by CAFs has been observed and may lead to CD4+ T cell activation and suppression of CD8+ T cells.
“More recently, antigen cross presentation by CAFs has been observed117, and this may lead to CD4+ T cell activation and suppression of CD8+ T cells118.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [118]
Fibroblasts can boost angiogenesis in in vitro assays.
“fibroblasts can boost angiogenesis in in vitro assays, with exciting advances in the development of microfluidic angiogenesis models, and an increasing number of studies have shown how they can alter T cell functionality118,161,162.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [118]
The Methods describe fibroblast–T-cell co-cultures and collagen-gel contraction assays, but no in vitro angiogenesis assay or finding that fibroblasts boost angiogenesis (searched: angiogenesis, vascular sprouting, and tube formation). The Discussion instead supports the sentence’s later, citation-adjacent point that fibroblasts alter T-cell function. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCAFs show characteristics of activated fibroblasts and/or myofibroblasts, consistent with the chronic inflammation and mechanical tension in tumors.
“CAFs show characteristics of activated fibroblasts and/or myofibroblasts, consistent with the chronic inflammation and mechanical tension in tumors12,233,234.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [234]
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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 · see citing works
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 15,314 · 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
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 · 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
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
Sato, E., Olson, S. H., Ahn, J., Bundy, B. N., Nishikawa, H., Qian, F., Jungbluth, A. A., Frosina, D., Gnjatic, S., Ambrosone, C. B., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509182102 · Cited by 2,375 · see citing works
Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential
Sharma, P., & Allison, J. P. (2015) · Cell · doi:10.1016/j.cell.2015.03.030 · Cited by 2,345 · see citing works
Taube, J. M., Klein, A., Brahmer, J. R., Xu, H., Pan, X., Kim, J. H., Chen, L., Pardoll, D. M., Topalian, S. L., & Anders, R. A. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-3271 · Cited by 2,324 · 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
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072 · 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
Gooden, M., de Bock, G. D., Leffers, N., Daemen, T., & Nijman, H. W. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.189 · Cited by 1,229 · see citing works
Salmon, 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
B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells
Tseng, S.-Y., Otsuji, M., Gorski, K. S., Huang, X., Slansky, J. E., Pai, S. I., Shalabi, A., Shin, T., Pardoll, D. M., & Tsuchiya, H. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.7.839 · Cited by 867 · see citing works
Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients
Baitsch, L., Baumgaertner, P., Devêvre, E., Raghav, S. K., Legat, A., Barba, L., Wieckowski, S., Bouzourene, H., Deplancke, B., Romero, P., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46102 · Cited by 845 · see citing works
The Differential Effects of Mutant <i>p53</i> Alleles on Advanced Murine Lung Cancer
Jackson, E. L., Olive, K. P., Tuveson, D. A., Bronson, R., Crowley, D., Brown, M., & Jacks, T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2193 · Cited by 553 · see citing works
Comito, G., Giannoni, E., Segura, C. P., Barcellos‐de‐Souza, P., Raspollini, M. R., Baroni, G., Lanciotti, M., Serni, S., & Chiarugi, P. (2013) · Oncogene · doi:10.1038/onc.2013.191 · Cited by 530 · see citing works
Induction of Lymphoidlike Stroma and Immune Escape by Tumors That Express the Chemokine CCL21
Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J., & Swartz, M. A. (2010) · Science · doi:10.1126/science.1185837 · Cited by 506 · see citing works
Self-citationFletcher, A. L., Lukacs‐Kornek, V., Reynoso, E. D., Pinner, S. E., Bellemare‐Pelletier, A., Curry, M. S., Collier, A.-R. Y., Boyd, R. L., & Turley, S. J. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20092642 · Cited by 341 · see citing works
Ishida, M., Iwai, Y., Tanaka, Y., Okazaki, T., Freeman, G. J., Minato, N., & Honjo, T. (2002) · Immunology Letters · doi:10.1016/s0165-2478(02)00142-6 · Cited by 280 · see citing works
Regulation of the anti-tumour immune response by cancer-associated fibroblasts
Harper, J. A., & Sainson, R. C. A. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.12.005 · Cited by 269 · see citing works
Nazareth, M. R., Broderick, L., Simpson-Abelson, M. R., Kelleher, R. J., Yokota, S. J., & Bankert, R. B. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.9.5552 · Cited by 259 · see citing works
Selective activation of p53-mediated tumour suppression in high-grade tumours
Junttila, M. R., Karnezis, A. N., Garcia, D. A., Madriles, F., Kortlever, R. M., Rostker, F., Swigart, L. B., Pham, D. M., Seo, Y., Evan, G. I., et al. (2010) · Nature · doi:10.1038/nature09526 · Cited by 244 · see citing works
Self-citationKamphorst, A. O., Guermonprez, P., Dudziak, D., & Nussenzweig, M. C. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001205 · Cited by 208 · see citing works
Hirosue, S., Vokali, E., Raghavan, V. R., Rincón-Restrepo, M., Lund, A. W., Corthésy-Henrioud, P., Capotosti, F., Halin, C., Hugues, S., & Swartz, M. A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302492 · Cited by 200 · see citing works
Tumor‐stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7
Jung, D., Che, Z. M., Kim, J., Kim, K., Kim, K., Williams, D. R., & Kim, J. (2009) · International Journal of Cancer · doi:10.1002/ijc.25060 · Cited by 186 · see citing works
PD-1 Ligand Expression by Human Colonic Myofibroblasts/Fibroblasts Regulates CD4+ T-Cell Activity
Pinchuk, I. V., Saada, J. I., Beswick, E. J., Boya, G., Qiu, S. M., Mifflin, R. C., Raju, G. S., Reyes, V. E., & Powell, D. W. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.07.016 · Cited by 185 · see citing works
Temporal dissection of p53 function in vitro and in vivo
Christophorou, M. A., Martı́n-Zanca, D., Soucek, L., Lawlor, E. R., Swigart, L. B., Verschuren, E. W., & Evan, G. I. (2005) · Nature Genetics · doi:10.1038/ng1572 · Cited by 182 · see citing works
Augsten, M., Sjöberg, E., Frings, O., Vorrink, S. U., Frijhoff, J., Olsson, E., Borg, Å., & Östman, A. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2740 · Cited by 165 · see citing works
Spadaro, F., Lapenta, C., Donati, S., Abalsamo, L., Barnaba, V., Belardelli, F., Santini, S. M., & Ferrantini, M. (2011) · Blood · doi:10.1182/blood-2011-06-363564 · Cited by 150 · see citing works
Wu, X., Zhang, H.-B., Xing, Q. R., Cui, J., Li, J., Li, Y., Tan, Y. Q., & Wang, S. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.416 · Cited by 120 · see citing works
Boeck, A. D., Hendrix, A., Maynard, D., Bockstal, M. V., Daniëls, A., Pauwels, P., Gespach, C. P., Bracke, M., & Wever, O. D. (2012) · PROTEOMICS · doi:10.1002/pmic.201200179 · Cited by 106 · see citing works
Basha, G., Lizee, G. A., Reinicke, A. T., Seipp, R. P., Omilusik, K. D., & Jefferies, W. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003247 · Cited by 85 · see citing works
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“One of the underlying mechanisms was the upregulation of FAS/FASL and PD-1/PDL2 on CD8+ T cells and CAFs, respectively, which drives the dysfunction of tumor-specific CD8+ T cells (Lakins et al., 2018).”
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- Authors
- Lakins, M. A., Ghorani, E., Munir, H., Martins, C. P., & Shields, J. D.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Shields, Jacqueline D.
- Venue
- Nature Communications
- Published
- 2018-03-05
- Volume
- 9
- Issue
- 1
- Pages
- 948-948
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5838096
- OpenAlex
- W2790543400
- Cited by
- 578
- References
- 36
- Citations by year
- 2026: 43 · 2025: 79 · 2024: 77 · 2023: 93 · 2022: 83 · 2021: 70 · 2020: 67 · 2019: 45 · 2018: 21
- FWCI
- 19.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (publishedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Medical Research Council (MC_UU_12022/5, MC_UU_12022/4)
- Cambridge Institute for Medical Research, University of Cambridge
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cancer-associated fibroblasts, CD8+ T cell suppression, tumor microenvironment, cross-presentation, PD-L2, Fas ligand, immune checkpoint, tumor stroma, T cell cytotoxicity, tumor immunosuppression
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Antigens, Neoplasm, Cell Survival, Cytotoxicity, Immunologic, Female, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes, Cytoprotection, Cross-Priming, Fas Ligand Protein, Proteolysis, Programmed Cell Death 1 Ligand 2 Protein
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