Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer
Open accessAbstract
Cancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1(+) CD11b(+) cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment.
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From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [175]
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BackgroundInfluentialOncogenic 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 · cited 1× · see citing works
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BackgroundMyeloid-derived suppressor cell heterogeneity and subset definition
Peranzoni, E., Zilio, S., Marigo, I., Dolcetti, L., Zanovello, P., Mandruzzato, S., & Bronte, V. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.01.021 · Cited by 634 · cited 2× · see citing works
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BackgroundFcRγ Activation Regulates Inflammation-Associated Squamous Carcinogenesis
Andreu, P., Johansson, M., Affara, N. I., Pucci, F., Tan, T., Junankar, S. R., Korets, L. V., Lam, J., Tawfik, D., DeNardo, D. G., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.019 · Cited by 591 · cited 4× · see citing works
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BackgroundInfluentialIL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses
Saenz, S. A., Siracusa, M. C., Perrigoue, J., Spencer, S. P., Urban, J. F., Tocker, J. E., Budelsky, A., Kleinschek, M. A., Kastelein, R. A., Kambayashi, T., et al. (2010) · Nature · doi:10.1038/nature08901 · Cited by 555 · see citing works
Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression
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“For example, the pro-inflammatory cytokine IL-1b has been implicated in MDSC pathophysiology such that fibrosarcoma or 4T1 mammary carcinoma cell lines engineered to secrete IL-1b grow more rapidly than control tumors upon implantation due to enhanced accumulation of Gr-1 CD11b and concomitant T cell suppression (Bunt…”
BackgroundStat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression
Fukuda, A., Wang, S. C., Morris, J. P., Folias, A. E., Liou, A., Kim, G. E., Akira, S., Boucher, K., Firpo, M., Mulvihill, S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.002 · Cited by 531 · cited 2× · see citing works
“In mice, IL-6 production can be induced in PDA tumor cells, or in pancreas epithelium harboring mutant Kras, but only after an acute inflammatory insult (Fukuda et al., 2011).”
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“…a heterogeneous population of myeloid cells including myelocytes, metamyelocytes, band and segmented neutrophils, and monocytoid cells (Figure 1D), consistent with previous observations of cancer-associated Gr-1 + CD11b + cells (Andreu et al., 2010; Bronte et al., 2000; Stairs et al., 2011).”
ResultSerafini, P., Carbley, R., Noonan, K. A., Tan, G. G. Y., Bronte, V., & Borrello, I. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0757 · Cited by 524 · cited 1× · see citing works
“In studies of implantable tumormodels, GM-CSF has been linked to the generation of Gr-1+ CD11b+ cells with immu- nosuppressive features (Bronte et al., 1999; Dolcetti et al., 2010; Morales et al., 2010; Serafini et al., 2004).”
BackgroundIL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice
Bronte, V., Serafini, P., Santo, C. D., Marigo, I., Tosello, V., Mazzoni, A., Segal, D. M., Staib, C., Löwel, M., Sutter, G., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.270 · Cited by 513 · cited 2× · see citing works
“Numerous studies have reported the expansion of Gr-1 CD11b cells in a variety of implantable tumor models and have demonstrated the ability of these myeloid cells to impair T cell responses in vitro (Bronte et al., 2003; Kusmartsev et al., 2004; Sinha et al., 2005).”
BackgroundInduction 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 · cited 2× · see citing works
“Recent studies have also linked the chemokine CCL21 to the appearance ofMDSC in the B16-F10 implantablemodel of melanoma (Shields et al., 2010), and other investigators have uncovered that IL-25 elicits a multipotent progenitor cell population in mucosal tissue that can differentiate into cells of various myeloid line…”
BackgroundSinha, P., Clements, V. K., & Ostrand‐Rosenberg, S. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.2.636 · Cited by 461 · cited 2× · see citing works
“Numerous studies have reported the expansion of Gr-1 CD11b cells in a variety of implantable tumor models and have demonstrated the ability of these myeloid cells to impair T cell responses in vitro (Bronte et al., 2003; Kusmartsev et al., 2004; Sinha et al., 2005).”
BackgroundBronte, V., Chappell, D. B., Apolloni, E., Cabrelle, A., Wang, M. L., Hwu, P., & Restifo, N. P. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.10.5728 · Cited by 404 · cited 4× · see citing works
“In studies of implantable tumormodels, GM-CSF has been linked to the generation of Gr-1 CD11b cells with immunosuppressive features (Bronte et al., 1999; Dolcetti et al., 2010; Morales et al., 2010; Serafini et al., 2004).”
BackgroundInfluentialRole 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 · cited 2× · see citing works
“Various terms have been used in the literature to describe Gr-1 + CD11b + cells, including immature myeloid cells (Kusmartsev and Gabrilovich, 2006) or myeloid derived suppressor cells (MDSC) (Gabrilovich et al., 2007).”
MethodMelani, C. C., Chiodoni, C., Forni, G., & Colombo, M. P. (2003) · Blood · doi:10.1182/blood-2003-01-0190 · Cited by 295 · cited 8× · see citing works
“Furthermore, normal pancreatic ductal cells also secreted VEGF (albeit somewhat less so than PDA cells) yet Gr-1 + CD11b + cells did not accumulate around normal ducts in vivo and conditioned media from normal ductal cells failed to support proliferation of c-kit + splenocytes into MDSC.”
BackgroundInfluentialSong, X., Krelin, Y., Dvorkin, T., Björkdahl, O., Segal, S., Dinarello, C. A., Voronov, E., & Apte, R. N. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.12.8200 · Cited by 290 · cited 2× · see citing works
“…implicated in MDSC pathophysi- ology such that fibrosarcoma or 4T1 mammary carcinoma cell lines engineered to secrete IL-1b grow more rapidly than control tumors upon implantation due to enhanced accumulation of Gr-1+ CD11b+ and concomitant T cell suppression (Bunt et al., 2006; Song et al., 2005).”
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“Other potential roles of Gr-1 + CD11b + cells in regulating tumor growth (Yang et al., 2004, 2008, 2011) appear therefore to be secondary or noncontributory to tumor growth, at least in this assay.”
BackgroundHuang, Y., Chen, X., Dikov, M. M., Novitskiy, S. V., Mosse, C. A., Li, Y., & Carbone, D. P. (2007) · Blood · doi:10.1182/blood-2007-01-065714 · Cited by 230 · cited 1× · see citing works
“VEGF and granulocyte colony-stimulating factor (G-CSF) have also been implicated in MDSC development (Gabrilovich et al., 1998; Huang et al., 2007; Roland et al., 2009; Dolcetti et al., 2010).”
BackgroundMorales, J. K., Kmieciak, M., Knutson, K. L., Bear, H. D., & Manjili, M. H. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0622-8 · Cited by 214 · cited 2× · see citing works
“In studies of implantable tumormodels, GM-CSF has been linked to the generation of Gr-1 CD11b cells with immunosuppressive features (Bronte et al., 1999; Dolcetti et al., 2010; Morales et al., 2010; Serafini et al., 2004).”
BackgroundRoland, C. L., Lynn, K. D., Toombs, J. E., Dineen, S. P., Udugamasooriya, D. G., & Brekken, R. A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007669 · Cited by 210 · cited 1× · see citing works
“VEGF and granulocyte colony-stimulating factor (G-CSF) have also been implicated in MDSC development (Gabrilovich et al., 1998; Huang et al., 2007; Roland et al., 2009; Dolcetti et al., 2010).”
BackgroundStairs, D. B., Bayne, L. J., Rhoades, B., Vega, M. E., Waldron, T. J., Kalabis, J., Klein–Szanto, A. J., Lee, J., Katz, J. P., Diehl, J. A., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.02.007 · Cited by 195 · cited 2× · 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).”
BackgroundResultSelf-citationMa, G., Pan, P., Eisenstein, S. G., Divino, C. M., Lowell, C. A., Takai, T., & Chen, S. (2011) · Immunity · doi:10.1016/j.immuni.2011.02.004 · Cited by 175 · cited 1× · see citing works
“…2C) and produced high levels of nitrite upon culture (Figure 2D), suggesting expression of inducible nitric oxide synthase (iNOS); both arginase and iNOS have been previously linked to immunosuppression by Gr-1 + CD11b + cells in tumor-bearing mice (Bronte and Zanovello, 2005; Ma et al., 2011).”
BackgroundClark, C. E., Beatty, G. L., & Vonderheide, R. H. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.09.037 · Cited by 157 · cited 2× · see citing works
“Leukocytes infiltrating PDA lesions are predominantly derived from the innate immune system and coordinate a network of local immune suppression (Clark et al., 2007, 2009).”
BackgroundSelf-citationBellone, G., Carbone, A., Smirne, C., Scirelli, T., Buffolino, A., Novarino, A., Stacchini, A., Bertetto, O., Palestro, G., Sorio, C., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.5.3448 · Cited by 136 · cited 4× · see citing works
“Indeed, our data are consistent with those of previous studies demonstrating IL-6 production primarily by stromal cells, not the tumor, in mouse models (Lesina et al., 2011) as well as human PDA (Bellone et al., 2006; Lesina et al., 2011).”
BackgroundResultInfluentialOverexpression of Interleukin-1β in the Murine Pancreas Results in Chronic Pancreatitis
Marrache, F., Tu, S. P., Bhagat, G., Pendyala, S., Österreicher, C. H., Gordon, S. A. K., Ramanathan, V., Penz-Österreicher, M., Betz, K. S., Song, Z., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.078 · Cited by 105 · cited 1× · see citing works
“Overexpression of IL-1b in the mouse pancreas results in pancreatitis but interestingly, not PanIN or PDA (Marrache et al., 2008).”
BackgroundA dual role for the immune response in a mouse model of inflammation-associated lung cancer
Dougan, M. L., Li, D., Neuberg, D. S., Mihm, M. C., Googe, P. B., Wong, K., & Dranoff, G. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44796 · Cited by 92 · cited 2× · see citing works
“In mice with combined loss of IFN-g, IL-3, and GM-CSF, lung carcinomas develop at a high frequency and exhibit an infiltrate of Gr-1 + CD11b + leukocytes (Dougan et al., 2011).”
BackgroundMeCP2/H3meK9 are involved in IL-6 gene silencing in pancreatic adenocarcinoma cell lines
Dandrea, M., Donadelli, M., Costanzo, C., Scarpa, A., & Palmieri, M. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp723 · Cited by 61 · cited 1× · see citing works
“In addition, IL-6 expression in tumors may be silenced by DNA methylation (Dandrea et al., 2009).”
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Tumor microenvironment and therapeutic response
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“In particular, pancreatic can- cer has been described to express GM-CSF, and the role of this growth factor in inducing immunosuppressive myeloid-derived suppressor cells in mouse models has been reported (Bayne et al., 2012; Dolcetti et al., 2010; Bronte et al., 2000).”
BackgroundPancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
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“For example, in response to lipopolysaccharide, CSF2-derived macrophages preferentially produce IL6, IL12, and TNFa, whereas CSF1-derived macrophages produce IL10 and CCL-2, but not IL12.”
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“In addition, cancer stem cells have been implicated in TME-mediated signaling processes, such as immune modulation and the formation of inflammatory niches [18,38,39].”
BackgroundImmune cell promotion of metastasis
Kitamura, T., Qian, B.-Z., & Pollard, J. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3789 · Cited by 1,158 · see citing works
History of myeloid-derived suppressor cells
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KRAS Mutation: From Undruggable to Druggable in Cancer
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“VEGF is a key factor driving the formation of the typically aberrant tumor vasculature and thereby endothelial anergy (Motz and Coukos, 2011), while GM-CSF is an important mediator in the recruitment and maintenance of myeloid suppressor cells in tumor tissues (Bayne et al., 2012).”
BackgroundTargeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
Jiang, H., Hegde, S., Knolhoff, B. L., Zhu, Y., Herndon, J. M., Meyer, M. A., Nywening, T. M., Hawkins, W. G., Shapiro, I. M., Weaver, D. T., et al. (2016) · Nature Medicine · doi:10.1038/nm.4123 · Cited by 1,060 · see citing works
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Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet?
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The Spleen in Local and Systemic Regulation of Immunity
Bronte, V., & Pittet, M. J. (2013) · Immunity · doi:10.1016/j.immuni.2013.10.010 · Cited by 1,078 · see citing works
“Splenic pDCs are conditioned by soluble factors (like TGF-b) released from macrophages processing apoptotic material and contribute to antigen tolerance, e.g., in the context of allogeneic bone marrow transplantation (Bonnefoy et al., 2011).”
BackgroundMyeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected
Marvel, D., & Gabrilovich, D. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80005 · Cited by 1,054 · see citing works
Pancreatic cancer stroma: an update on therapeutic targeting strategies
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“Although TAMs are the most prevalent of these cells, 2 recent reports showed that G-MDSCs mobilized by tumor-derived granulocyte macrophage colony-stimulating factor (GM-CSF) can also suppress CTL activation in PDAC tumors (30, 31).”
BackgroundThe complex role of tumor-infiltrating macrophages
Christofides, A., Strauss, L., Yeo, A. T., Cao, C., Charest, A., & Boussiotis, V. A. (2022) · Nature Immunology · doi:10.1038/s41590-022-01267-2 · Cited by 869 · see citing works
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“Recent studies have described the contribution of MDSCs to pancreatic cancer progression (Bayne et al., 2012), and the accumulation of MDSCs in patients with advanced pancreatic cancer correlates with disease stage (Diaz-Montero et al., 2009).”
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
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Obesity, Inflammation, and Cancer
Deng, T., Lyon, C. J., Bergin, S. M., Caligiuri, M. A., & Hsueh, W. A. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044359 · Cited by 801 · see citing works
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“We and others have reported that PDA tumor-cell-derived GM-CSF promotes myeloid cell mobilization which suppresses anti-tumor immunity (Bayne et al., 2012; Pylayeva-Gupta et al., 2012).”
Self-citationObstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies
Anderson, K. G., Stromnes, I. M., & Greenberg, P. D. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.02.008 · Cited by 706 · see citing works
New horizons in tumor microenvironment biology: challenges and opportunities
Chen, F., Zhuang, X., Lin, L., Yu, P., Wang, Y., Shi, Y., Hu, G., & Sun, Y. (2015) · BMC Medicine · doi:10.1186/s12916-015-0278-7 · Cited by 704 · see citing works
“The myeloid-derived suppressor cell (MDSC) population which encompasses immature dendritic cells, neutrophils, monocytes, and early myeloid progenitors implicates tumor-initiated endocrine signaling to the immune system through multiple chemokines such as granulocyte-macrophage colony stimulating factor [19,20].”
BackgroundChallenges 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
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“These granulocytes are often referred to as granulocytic myeloid-derived suppressor cells (G-MDSC), and their importance has previously been shown in human and murine pancreatic cancer (11, 31).”
BackgroundTumor microenvironment participates in metastasis of pancreatic cancer
Ren, B., Cui, M., Yang, G., Wang, H., Feng, M., You, L., & Zhao, Y. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0858-1 · Cited by 590 · see citing works
CD40 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-citationStromal biology and therapy in pancreatic cancer: a changing paradigm
Neeße, A., Algül, H., Tuveson, D. A., & Gress, T. M. (2015) · Gut · doi:10.1136/gutjnl-2015-309304 · Cited by 562 · see citing works
“76 77 Tumour-derived GM-CSF promotes recruitment of myeloid progenitor cells to the surrounding stroma and subsequent differentiation into myeloid-derived suppressor cells (MDSCs).”
BackgroundUgel, S., Sanctis, F. D., Mandruzzato, S., & Bronte, V. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80006 · Cited by 563 · see citing works
“Moreover, KRAS-dependent release of GM-CSF primed CD11b+Gr1+ cells to suppress tumor-specific CD8+ T cells and promoted progression to invasive PDAC; only the blockade of either GM-CSF production or CD11b+Gr1+ cell activity restored antitumor immunity (47).”
BackgroundFerroptosis of tumour neutrophils causes immune suppression in cancer
Kim, R., Hashimoto, A., Markosyan, N., Tyurin, V. A., Tyurina, Y. Y., Kar, G., Fu, S., Sehgal, M., Garcia-Gerique, L., Kossenkov, A. V., et al. (2022) · Nature · doi:10.1038/s41586-022-05443-0 · Cited by 552 · see citing works
Self-citationEne–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
“PA N C R EA S infiltration defect.(22,23) Thus, we examined this population of immune cells in our experiments with ATRA-treated KPC mice but did not observe any changes in MDSC (CD11bþ) infiltrate.”
BackgroundResultInfluentialMace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B. J., McQuinn, C. W., Loftus, S. N., Nordquist, E., Cruz‐Monserrate, Z., Yu, L., Young, G. S., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-311585 · Cited by 535 · 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
“Clinical trials involving GVAX (allogeneic pancreatic cancer cells modified to express GM-CSF) alone and/or in combination with CRS207 (live attenuated Listeria monocytogenes expressing mesothelin) have shown positive outcomes and generated excitement among the immunotherapy community.”
InfluentialNywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., et al. (2017) · Gut · doi:10.1136/gutjnl-2017-313738 · Cited by 495 · see citing works
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“…ATCC CAT# CCL-127 SKNLP Gift from Dr. Brenner, Baylor College of Medicine, Houston TX N/A KPC-4662 Isolated by Dr. Vonderheide’s lab (Bayne et al., 2012; Hingorani et al., 2005) N/A SW626 ATCC CAT# HTB-78 SK-OV-3 ATCC CAT# HTB-77 CaoV-3 ATCC CAT# HTB-75 Raji ATCC CAT# CCL-86 PDAC-2…”
BackgroundWinograd, 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
“This model recapitulates the molecular, histologic and immune parameters of the human disease (39-43).”
BackgroundMethodInfluentialSelf-citationTumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
Sherman, M. H., & Beatty, G. L. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031621-024600 · Cited by 481 · see citing works
Self-citationGM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation
Dougan, M. L., Dranoff, G., & Dougan, S. K. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.022 · Cited by 463 · see citing works
Zhang, Y., Chandra, V., Riquelme, E. M., Dutta, P., Quesada, P. R., Rakoski, A. I., Zoltan, M. A., Arora, N., Baydogan, S., Horne, W. T., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20190354 · Cited by 446 · see citing works
A Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment
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Targeting B cell receptor signalling in cancer: preclinical and clinical advances
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Chun, E., Lavoie, S., Michaud, M., Gallini, C. A., Kim, J., Soucy, G., Odze, R., Glickman, J. N., & Garrett, W. S. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.024 · Cited by 402 · see citing works
“For example, ACA-produced granulocyte-macrophage colony-stimulating factor recruits immature myeloid cells that accumulate in pancreatic ductal ACAs in mice, thwarts CD8+T cell-mediated anti-tumor immunity, and alters splenic MDSC proliferation and function (Bayne et al., 2012).”
BackgroundMcAllister, 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
“Among these, GM-CSF and other soluble factors have recently been implicated in tumor-induced expansion and recruitment of immunosuppressive cell populations (Bayne et al., 2012; Pylayeva-Gupta et al., 2012), while IL-8 and the IL-6-Stat3 pathway contribute to the induction of a protumorigenic inflammatory microenviron…”
Mace, T. A., Ameen, Z., Collins, A., Wojcik, S. E., Mair, M., Young, G. S., Fuchs, J. R., Eubank, T. D., Frankel, W. L., Bekaii‐Saab, T., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4601 · Cited by 413 · see citing works
“This mixture of factors is likely to synergize with other cancer derived factors such as GM-CSF that promote MDSC accumulation in the tumor microenvironment (34, 35) or HMGB1 which regulates a positive feedback loop between autophagy, IL-6 and pSTAT3 (36).”
BackgroundBroadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities
Balachandran, V. P., Beatty, G. L., & Dougan, S. K. (2019) · Gastroenterology · doi:10.1053/j.gastro.2018.12.038 · Cited by 444 · see citing works
Self-citationImmune modulatory effects of oncogenic KRAS in cancer
Hamarsheh, S., Groß, O., Brummer, T., & Zeiser, R. (2020) · Nature Communications · doi:10.1038/s41467-020-19288-6 · Cited by 387 · see citing works
Roles for KRAS in Pancreatic Tumor Development and Progression
di Magliano, M. P., & Logsdon, C. D. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.01.071 · Cited by 397 · see citing works
Lin, H., Liu, C., Hu, A.-K., Zhang, D., Yang, H., & Mao, Y. Q. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01544-7 · Cited by 421 · see citing works
Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring
Shi, Y., Gao, W., Lytle, N. K., Huang, P., Yuan, X., Dann, A. M., Ridinger-Saison, M., DelGiorno, K. E., Antal, C. E., Liang, G., et al. (2019) · Nature · doi:10.1038/s41586-019-1130-6 · Cited by 431 · see citing works
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Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer
Halbrook, C. J., & Lyssiotis, C. A. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.12.006 · Cited by 394 · see citing works
Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF high neutrophils
Engblom, C., Pfirschke, C., Žilionis, R., Martins, J. D. S., Bos, S. A., Courties, G., Rickelt, S., Sévère, N., Baryawno, N., Faget, J., et al. (2017) · Science · doi:10.1126/science.aal5081 · Cited by 388 · see citing works
Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer
Kemp, S. B., Cheng, N., Markosyan, N., Sor, R., Kim, I.-K., Hallin, J., Shoush, J., Quinones, L., Brown, N. V., Bassett, J. B., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1066 · Cited by 370 · see citing works
“Next, we examined the effects of MRTX1133 on the TME in the autochthonous KPC/Y model.”
InfluentialSelf-citationTumor microenvironment and cancer therapy resistance
Sun, Y. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.07.044 · Cited by 384 · see citing works
Daley, D., Mani, V. R. K., Mohan, N., Akkad, N., Ochi, A., Heindel, D. W., Lee, K. B., Zambirinis, C. P., Pandian, G. S. D. B., Savadkar, S., et al. (2017) · Nature Medicine · doi:10.1038/nm.4314 · Cited by 383 · see citing works
ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis.
Condamine, T., Kumar, V., Ramachandran, I. R., Youn, J.-I., Celis, E., Finnberg, N., El-Deiry, W. S., Winograd, R., Vonderheide, R. H., English, N. R., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74056 · Cited by 365 · see citing works
“KPC mice were described previously (52).”
Self-citationJang, J., Hajdu, C. H., Liot, C., Miller, G., Dustin, M. L., & Bar‐Sagi, D. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.062 · Cited by 373 · see citing works
“This is an open access article under the CC BY-NC-ND license (http:// recapitulate many of these immune signatures (Bayne et al., 2012; Clark et al., 2007; Daley et al., 2016).”
BackgroundTranscriptional regulation of myeloid-derived suppressor cells
Condamine, T., Mastio, J., & Gabrilovich, D. I. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.4ri0515-204r · Cited by 372 · see citing works
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“Indeed, the TIME of highly lethal, difficult-totreat, desmoplastic malignancies such as CCA or pancreatic ductal adenocarcinoma has an abundance of immunosuppressive myeloid cells including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) (9, 10).”
BackgroundTargeting the untargetable KRAS in cancer therapy
Liu, P., Wang, Y., & Li, X. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.03.002 · Cited by 366 · see citing works
IL35-Producing B Cells Promote the Development of Pancreatic Neoplasia
Pylayeva‐Gupta, Y., Das, S., Handler, J. S., Hajdu, C. H., Coffre, M., Koralov, S. B., & Bar‐Sagi, D. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0843 · Cited by 357 · see citing works
“For example, tumor associated macrophages and myeloid-derived suppressor cells have been shown to promote pancreatic tumorigenesis through the suppression of antitumor immunity via expression of heme oxygenase-1 and arginase, respectively (2-4).”
BackgroundStromal biology and therapy in pancreatic cancer: ready for clinical translation?
Neeße, A., Bauer, C. A., Öhlund, D., Lauth, M., Buchholz, M., Michl, P., Tuveson, D. A., & Gress, T. M. (2018) · Gut · doi:10.1136/gutjnl-2018-316451 · Cited by 348 · see citing works
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“way by transplantable and spontaneous tumors has been linked to the generation of immunosuppressive MDSC.(48-50)”
BackgroundMethodSTING-induced regulatory B cells compromise NK function in cancer immunity
Li, S., Mirlekar, B., Johnson, B. M., Brickey, W. J., Wrobel, J. A., Yang, N., Song, D., Entwistle, S., Tan, X. M., Deng, M., et al. (2022) · Nature · doi:10.1038/s41586-022-05254-3 · Cited by 349 · see citing works
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Neutrophil phenotypes and functions in cancer: A consensus statement
Quail, D. F., Amulic, B., Aziz, M., Barnes, B. J., Eruslanov, E. B., Fridlender, Z. G., Goodridge, H. S., Granot, Z., Hidalgo, A., Anna Huttenlocher, A., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220011 · Cited by 336 · see citing works
“Additional studies have suggested a similar role for tumor- or stroma-derived GM-CSF in promoting the expansion of neutrophils and their progenitors in association with cancer progression (Bayne et al., 2012; Bronte et al., 1999; Bronte et al., 2003; Kohanbash et al., 2013; Wu et al., 2014).”
BackgroundPancreatic cancer: why is it so hard to treat?
Oberstein, P. E., & Olive, K. P. (2013) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x13478680 · Cited by 334 · see citing works
“Following activation, the principle upregulated cytokine is granulocyte-macrophage colonystimulating factor (GM-CSF), which was found to promote the recruitment and activation of immature myeloid progenitor cells to become myeloid derived suppressor cells [Bayne et al. 2012; Pylayeva-Gupta et al. 2012].”
BackgroundZhang, Y., Velez-Delgado, A., Mathew, E., Li, D., Mendez, F., Flannagan, K., Rhim, A. D., Simeone, D. M., Beatty, G. L., & di Magliano, M. P. (2016) · Gut · doi:10.1136/gutjnl-2016-312078 · Cited by 338 · see citing works
Self-citationCell death in pancreatic cancer: from pathogenesis to therapy
Chen, X., Zeh, H. J., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00486-6 · Cited by 338 · see citing works
Microenvironmental Determinants of Pancreatic Cancer
Heßmann, E., Buchholz, S., Demir, İ. E., Singh, S. K., Gress, T. M., Ellenrieder, V., & Neeße, A. (2020) · Physiological Reviews · doi:10.1152/physrev.00042.2019 · Cited by 328 · see citing works
Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity
Stromnes, I. M., Brockenbrough, J. S., Izeradjene, K., Carlson, M. A., Cuevas, C. M., Simmons, R. M., Greenberg, P. D., & Hingorani, S. R. (2014) · Gut · doi:10.1136/gutjnl-2013-306271 · Cited by 332 · see citing works
“We observed that neither splenic nor tumour-derived Gr-MDSC survived after 24 h of culture in standard media as indicated by the collapse of cellular integrity and the appearance of pyknotic nuclei and cell debris ( fi gure 3A).”
Influentialγδ 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
T helper 17 cells play a critical pathogenic role in lung cancer
Chang, S. H., Mirabolfathinejad, S. G., Katta, H., Cumpian, A. M., Gong, L., Caetano, M. S., Moghaddam, S. J., & Dong, C. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1319051111 · Cited by 326 · see citing works
“Also, oncogenic K-ras–induced GM-CSF is capable of inducing proliferation and differentiation of c-kit+ Lineage– precursors into functional MDSC (38, 39).”
BackgroundInfluentialMyeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis
Waight, J. D., Netherby, C. S., Hensen, M. L., Miller, A., Hu, Q., Liu, S., Bogner, P. N., Farren, M. R., Lee, K. P., Liu, K., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68189 · Cited by 324 · see citing works
Role of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma
Zheng, L., Xue, J., Jaffee, E. M., & Habtezion, A. (2013) · Gastroenterology · doi:10.1053/j.gastro.2012.12.042 · Cited by 323 · see citing works
Role of the tumor microenvironment in tumor progression and the clinical applications (Review)
YUAN, Y., JIANG, Y.-C., SUN, C.-K., & CHEN, Q.-M. (2016) · Oncology Reports · doi:10.3892/or.2016.4660 · Cited by 320 · see citing works
Monocytes in the Tumor Microenvironment
Ugel, S., Canè, S., Sanctis, F. D., & Bronte, V. (2021) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012418-013058 · Cited by 316 · see citing works
The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion
Globig, A.-M., Zhao, S., Roginsky, J., Maltez, V. I., Güiza, J., Avina-Ochoa, N., Heeg, M., Hoffmann, F. A., Chaudhary, O., Wang, J., et al. (2023) · Nature · doi:10.1038/s41586-023-06568-6 · Cited by 317 · see citing works
Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot
Ullman, N. A., Burchard, P. R., Dunne, R. F., & Linehan, D. C. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02616 · Cited by 303 · see citing works
Beatty, G. L., Winograd, R., Evans, R. A., Long, K. B., Luque, S. L., Lee, J. W., Clendenin, C. J., Gladney, W. L., Knoblock, D. M., Guirnalda, P. D., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.010 · Cited by 293 · see citing works
Self-citationYang, X., Lu, Y., Hang, J., Zhang, J., Zhang, T., Huo, Y., Liu, J., Lai, S., Luo, D., Wang, L., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0111 · Cited by 278 · see citing works
Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer
Dilly, J., Hoffman, M. T., Abbassi, L., Li, Z., Paradiso, F., Parent, B. D., Hennessey, C. J., Jordan, A. C., Morgado, M., Dasgupta, S., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0177 · Cited by 276 · see citing works
“Consistent with prior work showing that oncogenic KRAS drives production of GM-CSF and recruitment of granulocytes (61, 62), we found that MRTX1133 treatment resulted in reduced immuno-suppressive growth factors and reduced infiltration of granulocytic and monocytic myeloid-derived suppressor cells…”
Self-citationLong, K. B., Gladney, W. L., Tooker, G. M., Graham, K. L., Fraietta, J. A., & Beatty, G. L. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1032 · Cited by 276 · see citing works
Self-citationFreed-Pastor, W. A., Lambert, L. J., Ely, Z. A., Pattada, N. B., Bhutkar, A., Eng, G., Mercer, K. L., Garcia, A. P., Lin, L., Rideout, W. M., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.07.007 · Cited by 273 · see citing works
Mao, Y., Sarhan, D., Steven, A., Seliger, B., Kiessling, R. W., & Lundqvist, A. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0635 · Cited by 274 · see citing works
Cancer immune evasion, immunoediting and intratumour heterogeneity
Roerden, M., & Spranger, S. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-024-01111-8 · Cited by 285 · see citing works
Remark, R., Becker, C., Gomez, J. E., Damotte, D., Dieu‐Nosjean, M., Sautès‐Fridman, C., Fridman, W. H., Powell, C. A., Altorki, N. K., Mérad, M., et al. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201409-1671pp · Cited by 270 · see citing works
“In a model of pancreatic cancer, it has been proposed that oncogenic Kras restrained the antitumor immune response through the production of granulocytemacrophage colony-stimulating factor and the subsequent suppression of T-cell immunity (67).”
BackgroundGM-CSF: A Double-Edged Sword in Cancer Immunotherapy
Kumar, A., Khani, A. T., Ortiz, A. S., & Swaminathan, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.901277 · Cited by 277 · see citing works
“In PDAC, MDSCs that develop from tumor-derived GM-CSF also inhibit antigen-specific CD8 T cell responses (153).”
Background
- Authors
- Bayne, L. J., Beatty, G. L., Jhala, N., Clark, C. E., Rhim, A. D., Stanger, B. Z., & Vonderheide, R. H.
- Affiliations
- University of Pennsylvania (US)
- Abramson Cancer Center (US)
- Corresponding author
- Vonderheide, Robert H.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 21
- Issue
- 6
- Pages
- 822-835
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3575028
- OpenAlex
- W2129176863
- Cited by
- 947
- References
- 45
- Citations by year
- 2026: 49 · 2025: 44 · 2024: 47 · 2023: 72 · 2022: 83 · 2021: 82 · 2020: 91 · 2019: 63 · 2018: 59 · 2017: 65 · 2016: 78 · 2015: 60 · 2014: 68 · 2013: 77 · 2012: 9
- FWCI
- 29.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 411 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Abramson Family Cancer Research Institute
- National Institutes of Health (K08 088945, K12 CA076931)
- American Gastroenterological Association
- Cancer Research Institute
- Gabrielle’s Angel Foundation for Cancer Research
- Pennsylvania Department of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- GM-CSF, pancreatic ductal adenocarcinoma, tumor inflammation, myeloid cells, tumor microenvironment, T cell suppression, CD8+ T cells, tumor immune evasion, tumor-derived cytokines
- MeSH terms
- Adenocarcinoma, Animals, Humans, Immunohistochemistry, Inflammation, Mice, Transgenic, Pancreatic Neoplasms, T-Lymphocytes, Granulocyte-Macrophage Colony-Stimulating Factor, Mice, Knockout, CD8-Positive T-Lymphocytes, Models, Immunological, Receptors, Chemokine, Carcinoma, Pancreatic Ductal, Myeloid Cells, RNA Interference, CD11b Antigen, Cell Line, Tumor, Mice, Tumor Microenvironment
About these checks
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