Dynamics of the immune reaction to pancreatic cancer from inception to invasion
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Abstract
The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early “elimination phase” of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer. [Cancer Res 2007;67(19):9518–27]
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The PDAC TME features abundant immune-suppressive myeloid cells and regulatory T cells and scarce cytotoxic lymphocytes.
“The PDAC TME features abundant immune-suppressive myeloid cells and regulatory T cells (T reg cells) and scarce cytotoxic lymphocytes (Clark et al., 2007; Vonderheide and Bayne, 2013).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Clark et al., 2007
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Cites
Control of Regulatory T Cell Development by the Transcription Factor <i>Foxp3</i>
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187 · see citing works
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003) · Nature Immunology · doi:10.1038/ni904 · Cited by 7,745 · 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
Park, J., Adoro, S., Guinter, T. I., Erman, B., Alag, A., Catálfamo, M., Kimura, M. Y., Cui, Y., Lucas, P. J., Gress, R. E., et al. (2010) · Nature Immunology · doi:10.1038/ni.1840 · Cited by 5,835 · see citing works
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.3.1151 · Cited by 5,608 · see citing works
Jemal, A., Siegel, R. L., Ward, E. M., Murray, T., Xu, J., Smigal, C., & Thun, M. J. (2006) · CA A Cancer Journal for Clinicians · doi:10.3322/canjclin.56.2.106 · Cited by 5,309 · see citing works
Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., et al. (2004) · Nature Medicine · doi:10.1038/nm1093 · Cited by 5,151 · see citing works
Intratumoral 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 · see citing works
Tumour-educated macrophages promote tumour progression and metastasis
Pollard, J. W. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1256 · Cited by 3,365 · see citing works
The Three Es of Cancer Immunoediting
Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104803 · Cited by 3,087 · see citing works
IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity
Shankaran, V., Ikeda, H., Bruce, A. T., White, J. M., Swanson, P. E., Old, L. J., & Schreiber, R. D. (2001) · Nature · doi:10.1038/35074122 · Cited by 2,896 · see citing works
Sakaguchi, S. (2005) · Nature Immunology · doi:10.1038/ni1178 · Cited by 2,669 · see citing works
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609 · see citing works
Self-citationPreinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
Self-citationRegulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J., Farr, A. G., & Rudensky, A. Y. (2005) · Immunity · doi:10.1016/j.immuni.2005.01.016 · Cited by 2,255 · see citing works
CD4+CD25+ suppressor T cells: more questions than answers
Shevach, E. M. (2002) · Nature reviews. Immunology · doi:10.1038/nri821 · Cited by 2,097 · see citing works
Sakaguchi, S., Sakaguchi, N., Shimizu, J., Yamazaki, S., Sakihama, T., Itoh, M., Kuniyasu, Y., Nomura, T., Toda, M., & Takahashi, T. (2001) · Immunological Reviews · doi:10.1034/j.1600-065x.2001.1820102.x · Cited by 1,505 · see citing works
Shimizu, J., Yamazaki, S., & Sakaguchi, S. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.10.5211 · Cited by 1,491 · see citing works
Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice
Kaplan, D. H., Shankaran, V., Dighe, A. S., Stockert, E., Aguet, M., Old, L. J., & Schreiber, R. D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7556 · Cited by 1,465 · see citing works
Almand, B., Clark, J. I., Nikitina, E., van Beynen, J., English, N. R., Knight, S. C., Carbone, D. P., & Gabrilovich, D. I. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.1.678 · Cited by 1,340 · see citing works
Cancer despite immunosurveillance: immunoselection and immunosubversion
Zitvogel, L., Tesniere, A., & Kroemer, G. (2006) · Nature reviews. Immunology · doi:10.1038/nri1936 · Cited by 1,324 · see citing works
CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer.
Naito, Y., Saito, K., Shiiba, K., Ohuchi, A., Saigenji, K., Nagura, H., & Ohtani, H. (1998) · PubMed · Cited by 1,193 · see citing works
Yang, L., DeBusk, L. M., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., Matrisian, L. M., Carbone, D. P., & Lin, P. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.08.031 · Cited by 1,140 · see citing works
Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T., & Nakayama, E. (1999) · PubMed · Cited by 1,062 · see citing works
Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R., & Albelda, S. M. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0883 · Cited by 1,054 · see citing works
Role of tumor-associated macrophages in tumor progression and invasion
Mantovani, A., Schioppa, T., Porta, C., Allavena, P., & Sica, A. (2006) · Cancer and Metastasis Reviews · doi:10.1007/s10555-006-9001-7 · Cited by 885 · see citing works
Smyth, M. J., Dunn, G. P., & Schreiber, R. D. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)90001-7 · Cited by 872 · see citing works
Progression model for pancreatic cancer.
Hruban, R. H., Goggins, M., Parsons, J., & Kern, S. E. (2000) · PubMed · Cited by 872 · see citing works
Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis
Sparmann, A., & Bar‐Sagi, D. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.028 · Cited by 854 · see citing works
Dutton, R. W., Bradley, L. M., & Swain, S. L. (1998) · Annual Review of Immunology · doi:10.1146/annurev.immunol.16.1.201 · Cited by 832 · 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
Cancer--A Biological Approach: I. The Processes Of Control. II. The Significance of Somatic Mutation
Burnet, M. (1957) · BMJ · doi:10.1136/bmj.1.5022.779 · Cited by 811 · see citing works
Visualization of Specific B and T Lymphocyte Interactions in the Lymph Node
Garside, P., Ingulli, E. G., Merica, R. R., Johnson, J. G., Noelle, R. J., & Jenkins, M. K. (1998) · Science · doi:10.1126/science.281.5373.96 · Cited by 774 · see citing works
Serafini, P., Borrello, I., & Bronte, V. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.07.005 · Cited by 758 · see citing works
Natural regulatory T cells: mechanisms of suppression
Miyara, M., & Sakaguchi, S. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.01.003 · Cited by 714 · see citing works
Dighe, A. S., Richards, E., Old, L. J., & Schreiber, R. D. (1994) · Immunity · doi:10.1016/1074-7613(94)90087-6 · Cited by 663 · see citing works
den Eynde, B. J. V., & van der Bruggen, P. (1997) · Current Opinion in Immunology · doi:10.1016/s0952-7915(97)80050-7 · Cited by 629 · see citing works
Mechanism of Immune Dysfunction in Cancer Mediated by Immature Gr-1+ Myeloid Cells
Gabrilovich, D. I., Velders, M. P., Sotomayor, E. M., & Kast, W. M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.9.5398 · Cited by 538 · see citing works
Decreased tumor surveillance in perforin-deficient mice.
van den Broek, M. F., Kägi, D., OSSENDORP, F. A., Toes, R. E. M., Vamvakas, S. M., Lutz, W. K., Melief, C. J. M., Zinkernagel, R. M., & Hengartner, H. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.5.1781 · Cited by 513 · see citing works
Burnet, M. (1957) · BMJ · doi:10.1136/bmj.1.5023.841 · Cited by 505 · see citing works
Kusmartsev, S. A., Cheng, F., Yu, B., Nefedova, Y., Sotomayor, E. M., Lush, R. M., & Gabrilovich, D. I. (2003) · PubMed · Cited by 460 · see citing works
Hruban, R., Adsay, N., Albores-saavedra, J., Anver, M., Biankin, A., Boivin, G. P., Furth, E., Furukawa, T., Klein, A., Klimstra, D., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2168 · Cited by 411 · see citing works
Self-citationKusmartsev, S. A., Yu, L., & Chen, S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.2.779 · Cited by 355 · see citing works
Role Of Immature Myeloid Cells in Mechanisms of Immune Evasion In Cancer
Kusmartsev, S. A., & Gabrilovich, D. I. (2005) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-005-0048-z · Cited by 346 · see citing works
Bronte, V., Wang, M. L., Overwijk, W. W., Surman, D. R., Pericle, F., Rosenberg, S. A., & Restifo, N. P. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.10.5313 · Cited by 312 · see citing works
K-ras activation generates an inflammatory response in lung tumors
Ji, H., Houghton, A. M., Mariani, T. J., Perera, S. A., Kim, C. B. Y., Padera, R. F., Tonon, G., McNamara, K. L., Marconcini, L. A. L., Hezel, A. F., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209237 · Cited by 271 · see citing works
Vesalainen, S., Lipponen, P., Talja, M. T., & Syrjänen, K. J. (1994) · European Journal of Cancer · doi:10.1016/0959-8049(94)e0159-2 · Cited by 254 · see citing works
Adjustment of children and adolescents to parental cancer: Parents' and children's perspectives
Welch, A. S., Wadsworth, M. E., & Compas, B. E. (1996) · Cancer · doi:10.1002/(sici)1097-0142(19960401)77:7 · Cited by 217 · see citing works
Dhodapkar, M. V., Krasovsky, J., Osman, K., & Geller, M. D. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20031030 · Cited by 217 · see citing works
Immunotherapy for pancreatic cancer — science driving clinical progress
Laheru, D. A., & Jaffee, E. M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1630 · Cited by 202 · see citing works
Emerging possibilities in the development and function of regulatory T cells
Wing, K., Fehervari, Z. T., & Sakaguchi, S. (2006) · International Immunology · doi:10.1093/intimm/dxl044 · Cited by 154 · see citing works
Resection of Solid Tumors Reverses T Cell Defects and Restores Protective Immunity
Salvadori, S., Martinelli, G. P., & Zier, K. S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.4.2214 · Cited by 143 · see citing works
B cell migration and interactions in the early phase of antibody responses
Okada, T., & Cyster, J. G. (2006) · Current Opinion in Immunology · doi:10.1016/j.coi.2006.02.005 · Cited by 139 · see citing works
Ductal Pancreatic Cancer in Humans and MicePreprint
Tuveson, D. A., & Hingorani, S. R. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.040 · Cited by 86 · see citing works
Self-citationMouse models of pancreatic cancer
Leach, S. D. (2004) · Cancer Cell · doi:10.1016/s1535-6108(03)00337-4 · Cited by 72 · see citing works
Macrophage Infiltration and Angiogenesis in Human Malignancy
Knowles, H. J., Leek, R., & Harris, A. L. (2004) · Novartis Foundation symposium · doi:10.1002/0470856734.ch14 · Cited by 69 · see citing works
Volm, M., Koomägi, R., Stammler, G., Rittgen, W., Zintl, F., & Sauerbrey, A. (1997) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19971021)74:5 · Cited by 41 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Burnet F. Cancer-a biological approach. Br Med J 1957; 1:841-7.
- Clemente CG, Mihm MC, Jr., Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996;77: 1303-10.
- Marrogi AJ, Munshi A, Merogi AJ, et al. Study of tumor infiltrating lymphocytes and transforming growth factor-h as prognostic factors in breast carcinoma. Int J Cancer 1997;74:492-501.
Cited by
Sorted by citations
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
EMT and Dissemination Precede Pancreatic Tumor Formation
Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., Reichert, M., Beatty, G. L., Rustgi, A. K., Vonderheide, R. H., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.025 · Cited by 2,136 · see citing works
Self-citationKleeff, J., Korc, M., Apte, M., La Vecchia, C., Johnson, C. D., Biankin, A. V., Neale, R. E., Tempero, M., Tuveson, D. A., Hruban, R. H., et al. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.22 · Cited by 1,982 · see citing works
Self-citationRAS oncogenes: weaving a tumorigenic web
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3106 · Cited by 1,789 · see citing works
Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., Mohan, N., Aykut, B., Usyk, M., Torres, L. E., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1134 · Cited by 1,400 · see citing works
The Pancreas Cancer Microenvironment
Feig, C., Gopinathan, A., Neesse, A., Chan, D. S., Cook, N., & Tuveson, D. A. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3114 · Cited by 1,316 · see citing works
Self-citationBayne, L. J., Beatty, G. L., Jhala, N., Clark, C. E., Rhim, A. D., Stanger, B. Z., & Vonderheide, R. H. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.025 · Cited by 947 · see citing works
“…in patients with the same disease—the role of these cells remains controversial particularly with regard to the in vivo relevance of the T cell suppressive qualities that are typically demonstrated in vitro (Andreu et al., 2010; Clark et al., 2007; Melani et al., 2003; Stairs et al., 2011).”
BackgroundInfluentialSelf-citationOncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G., & Bar-Sagi, D. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.024 · Cited by 721 · see citing works
Challenges and Opportunities for Pancreatic Cancer Immunotherapy
Bear, A. S., Vonderheide, R. H., & O'Hara, M. H. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.08.004 · Cited by 674 · see citing works
Self-citationCD40 agonist antibodies in cancer immunotherapy
Vonderheide, R. H. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-062518-045435 · Cited by 544 · see citing works
Self-citationType 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer
Hart, P. A., Bellin, M. D., Andersen, D. K., Bradley, D., Cruz-Monserrate, Z., Forsmark, C. E., Goodarzi, M. O., Habtezion, A., Korc, M., Kudva, Y. C., et al. (2016) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(16)30106-6 · Cited by 551 · see citing works
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
Winograd, R., Byrne, K. T., Evans, R. A., Odorizzi, P. M., Meyer, A. R. L., Bajor, D. L., Clendenin, C., Stanger, B. Z., Furth, E. E., Wherry, E. J., et al. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0215 · Cited by 459 · see citing works
Self-citationTan, M. C. B., Goedegebuure, P. S., Belt, B. A., Flaherty, B., Sankpal, N., Gillanders, W. E., Eberlein, T. J., Hsieh, C.-S., & Linehan, D. C. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.182.3.1746 · Cited by 450 · see citing works
McAllister, F., Bailey, J. M., Alsina, J., Nirschl, C. J., Sharma, R., Fan, H., Rattigan, Y., Roeser, J. C., Lankapalli, R. H., Zhang, H., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.014 · Cited by 405 · see citing works
Tsai, S., McOlash, L., Palen, K., Johnson, B., Duris, C., Yang, Q., Dwinell, M. B., Hunt, B., Evans, D. B., Gershan, J., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-4238-4 · Cited by 400 · see citing works
Zhang, Y., Lazarus, J., Steele, N. G., Yan, W., Lee, H.-J., Nwosu, Z. C., Halbrook, C. J., Menjivar, R. E., Kemp, S. B., Sirihorachai, V. R., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0958 · Cited by 385 · see citing works
Zhang, W., Nandakumar, N., Shi, Y., Manzano, M., Smith, A., Graham, G., Gupta, S., Vietsch, E. E., Laughlin, S. Z., Wadhwa, M., et al. (2014) · Science Signaling · doi:10.1126/scisignal.2005049 · Cited by 360 · see citing works
Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity
Hutton, C., Heider, F., Blanco-Gomez, A., Banyard, A., Kononov, A., Zhang, X., Karim, S., Paulus-Hock, V., Watt, D., Steele, N., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.06.017 · Cited by 337 · see citing works
Blando, J., Sharma, A., Higa, M. G., Zhao, H., Vence, L., Yadav, S. S., Kim, J., Sepulveda, A. M., Sharp, M., Maitra, A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811067116 · Cited by 334 · see citing works
γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation
Daley, D., Zambirinis, C. P., Seifert, L., Akkad, N., Mohan, N., Werba, G., Barilla, R., Torres-Hernandez, A., Hundeyin, M., Mani, V. R. K., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.046 · Cited by 329 · see citing works
Recent advances in exosome-mediated nucleic acid delivery for cancer therapy
Zhang, Y., Liu, Q., Zhang, X., Huang, H., Tang, S., Chai, Y., Xu, Z., Li, M., Chen, X., Liu, J., et al. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01472-z · Cited by 306 · see citing works
Hosein, A. N., Huang, H., Wang, Z., Parmar, K., Du, W., Huang, J., Maitra, A., Olson, E., Verma, U., & Brekken, R. A. (2019) · JCI Insight · doi:10.1172/jci.insight.129212 · Cited by 302 · see citing works
CD40 stimulation obviates innate sensors and drives T cell immunity in cancer
Byrne, K. T., & Vonderheide, R. H. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.058 · Cited by 282 · see citing works
Self-citationSHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Fedele, C., Li, S., Teng, K. W., Foster, C. J. R., Peng, D., Ran, H., Mita, P., Geer, M. J., Hattori, T., Koide, A., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201414 · Cited by 265 · see citing works
NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma
Daley, D., Mani, V. R., Mohan, N., Akkad, N., Pandian, G. S. D. B., Savadkar, S., Lee, K. B., Torres-Hernandez, A., Aykut, B., Diskin, B., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161707 · Cited by 244 · see citing works
Candido, J. B., Morton, J. P., Bailey, P., Campbell, A. D., Karim, S. A., Jamieson, T., Lapienyte, L., Gopinathan, A., Clark, W., McGhee, E. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.131 · Cited by 224 · see citing works
Dey, P., Li, J., Zhang, J., Chaurasiya, S., Strom, A., Wang, H., Liao, W.-T., Cavallaro, F., Denz, P., Bernard, V., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0297 · Cited by 213 · see citing works
Kemp, S. B., Carpenter, E. S., Steele, N. G., Donahue, K. L., Nwosu, Z. C., Pacheco, A., Velez-Delgado, A., Menjivar, R. E., Lima, F., The, S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3929 · Cited by 197 · see citing works
Ma, Y., Li, J., Wang, H., Chiu, Y., Kingsley, C. V., Fry, D., Delaney, S. N., Wei, S. C., Zhang, J., Maitra, A., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.03.018 · Cited by 154 · see citing works
Chemotherapy and tumor microenvironment of pancreatic cancer
Liu, Q., Liao, Q., & Zhao, Y. (2017) · Cancer Cell International · doi:10.1186/s12935-017-0437-3 · Cited by 120 · see citing works
Epithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108 · see citing works
Self-citationCD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice
Zhang, Y., Yan, W., Mathew, E., Bednar, F., Wan, S., Collins, M. A., Evans, R. A., Welling, T. H., Vonderheide, R. H., & di Magliano, M. P. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0016-t · Cited by 102 · see citing works
Self-citationLiu, H., Naxerova, K., Pinter, M., Incio, J., Lee, H., Shigeta, K., Ho, W. W., Crain, J. A., Jacobson, A., Michelakos, T., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0256 · Cited by 96 · see citing works
Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming
Velez-Delgado, A., Donahue, K. L., Brown, K. L., Du, W., Irizarry-Negron, V., Menjivar, R. E., Lasse Opsahl, E. L., Steele, N. G., The, S., Lazarus, J., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.016 · Cited by 91 · see citing works
Cell Volume Regulation in Epithelial Physiology and Cancer
Pedersen, S. F., Hoffmann, E. K., & Novak, I. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00233 · Cited by 94 · see citing works
Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer
Sivaram, N., McLaughlin, P. A., Han, H. V., Petrenko, O., Jiang, Y.-P., Ballou, L. M., Pham, K., Liu, C., van der Velden, A. W. M., & Lin, R. Z. (2019) · Journal of Clinical Investigation · doi:10.1172/jci123540 · Cited by 78 · see citing works
Jäkel, C., Bergmann, F., Toth, R., Assenov, Y., van der Duin, D., Strobel, O., Hank, T., Klöppel, G., Dorrell, C., Grompe, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01118-x · Cited by 69 · see citing works
McCubrey, J. A., Yang, L. V., Abrams, S. L., Steelman, L. S., Follo, M. Y., Cocco, L., Ratti, S., Martelli, A. M., Augello, G., & Cervello, M. (2022) · Cells · doi:10.3390/cells11142155 · Cited by 49 · see citing works
A 3D pancreatic tumor model to study T cell infiltration
Mollica, H., Teo, Y. J., Tan, A. S. M., Tan, D. Z. M., Decuzzi, P., Pavesi, A., & Adriani, G. (2021) · Biomaterials Science · doi:10.1039/d1bm00210d · Cited by 32 · see citing works
PDAC as an immune evasive disease: can 3D model systems aid to tackle this clinical problem?
Narayanan, S., Vicent, S., & Ponz-Sarvisé, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.787249 · Cited by 24 · see citing works
- Authors
- Clark, C. E., Hingorani, S. R., Mick, R., Combs, C., Tuveson, D. A., & Vonderheide, R. H.
- Affiliations
- Abramson Cancer Center (US)
- University of Washington (US)
- University of Pennsylvania (US)
- Venue
- Cancer Research
- Published
- 2007-10-01
- Volume
- 67
- Issue
- 19
- Pages
- 9518-9527
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2100519108
- Cited by
- 990
- References
- 57
- Citations by year
- 2026: 30 · 2025: 37 · 2024: 61 · 2023: 86 · 2022: 78 · 2021: 80 · 2020: 93 · 2019: 69 · 2018: 60 · 2017: 58 · 2016: 70 · 2015: 55 · 2014: 64 · 2013: 62 · 2012: 33
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pancreatic Cancer Action Network
- National Institutes of Health (5f31ai056672-02, C‐A111294, DK050306, CA15704)
- National Cancer Institute (CA101973, CA84291, CA 15704+, CA111294, U01CA084291, CA114028, R01CA101973, U01CA111294, K08CA114028, P30CA015704)
- National Institute of Allergy and Infectious Diseases (AI056672)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-050306, P30DK050306)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- pancreatic ductal adenocarcinoma, tumor surveillance, tumor immunology, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, tumor-infiltrating T cells, pancreatic carcinogenesis, immunosuppression, T cell proliferation inhibition, cancer immunotherapy
- MeSH terms
- Animals, Leukocytes, Macrophages, Pancreatic Neoplasms, Genes, ras, Lymphocytes, Tumor-Infiltrating, Disease Progression, Carcinoma, Pancreatic Ductal, T-Lymphocytes, Regulatory, Mice
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