Downloaded from http://gut.bmj.com/ on January 20, 2015 - Published by group.bmj.com
Commentary
Myeloid-derived suppressor cells in pancreatic cancer: more than a hidden barrier for antitumour immunity? Tim F Greten Myeloid-derived suppressor cells (MDSC) represent an immune cell subset with profound immune suppressor function. Initially described in 1978 as natural suppressor cells, this cell type has gained significant attention in recent years not only among tumour immunologists but also among medical oncologists interested both in developing new immune-based antitumour strategies and trying to understand how conventional non-immunological therapies affect antitumour immune responses.1 MDSC represent a mixture of immature cell types that accumulate in tumour-bearing mice and patients with cancer. Tumour-derived factors block the maturation of myeloid cells at different stages, leading to accumulation of these cells in tumours, as well as in the periphery. At least two different subsets of MDSC have been described in mice and men: monocytic and polymorphonuclear granulocytic MDSC, which can be identified as CD14+HLA-DRlo/neg and neg + lin CD11b HLA-DRneg in patients2 and as CD11b+Ly6G+ Ly6Clow or + neg hi CD11b Ly6G Ly6C in mice.3 An accumulation of MDSC has been described in multiple models of pancreatic cancer. We have been able to demonstrate an accumulation of MDSC in mice with premalignant lesions.4 Similarly, an accumulation of MDSC, regulatory T cells and tumour-associated macrophages has been described in KC mice, which express the KrasG12D allele under the pancreaticspecific promoter Pdx-1,5 suggesting that accumulation of MDSC is an early event during pancreatic cancer development. Oncogenic K-ras-induced GM-CSF production by pancreatic ductal epithelial cells, which can also be detected in human PanIn lesions, is required for the recruitment of CD11b+Gr1+ cells.6 7 Analysis of MDSC in peripheral blood from patients with pancreatic cancer8 9 corroborated findings obtained in different murine pancreatic cancer models and further stressed Correspondence to Professor Tim F Greten, Thoracic and Gastrointestinal Oncology Branch, Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; [email protected] 1690
the potential importance of this cell type in pancreatic cancer. Using genetically engineered mice, which express KrasG12D and mutatedTrp53 in the pancreas (KPC mice) and develop autochthonous pancreatic ductal adenocarcinoma, Dr Hingorani’s group went one step further and studied the function of specific MDSC subsets in pancreatic cancer both in vitro and in vivo.10 The authors observed a specific increase in the frequency of granulocytic CD11b+Gr-1highLy6cint MDSC from preinvasive to invasive pancreatic adenocarcinoma, suggesting that accumulation of granulocytic MDSC is a late event during tumour development. These granulocytic MDSC were not only potent T cell suppressors but were also more potent at inducing T cell apoptosis than their counterparts from spleen or bone marrow. Survival of granulocytic MDSC was dependent on GM-CSF released by tumour cells, corroborating previous studies that had already demonstrated a pivotal role for this cytokine in MDSC generation in mice with pancreatic cancer.6 7 Probably the most important results came from experiments in which the authors selectively depleted granulocytic MDSC in mice with invasive pancreatic adenocarcinoma. Interestingly, depletion of granulocytic MDSC led to fourfold to fivefold increase of monocytic MDSC, suggesting a homeostatic relationship between the two subsets. At first glance, it may have been disappointing to notice that depletion of granulocytic MDSC did not change tumour masses in treated mice but rather these tumours grew instead. It is not clear whether more time was needed so that activation of T cells can actually induce tumour responses. However, this tumour growth was accompanied by an influx of proliferating, activated, granzyme B+ CD8+ T cells in tumours, suggesting that depletion of granulocytic MDSC enhanced CD8-mediated antitumour immunity in mice with pancreatic adenocarcinoma. Some indications of a functional relevance for these findings came from the observation that depletion of granulocytic MDSC affected the stromal architecture and integrity of tumours. Increased apoptosis of tumour epithelial cells along with decreased extracellular
matrix deposition and the appearance of patent blood vessels were observed in treated mice. These studies have important implications for the field of those working on immunotherapy in general as well as those trying to develop better treatments for patients with pancreatic cancer. The authors very nicely demonstrated that premature conclusions should be avoided from the plain observation of tumour growth in immunotherapy settings. Thorough analysis of the primary tumour site revealed some novel and interesting insights on MDSC biology. First, granulocytic MDSC induced apoptosis in T cells, suggesting a previously unrecognised mode of suppressor function. Second, the authors describe a novel mechanism of how granulocytic MDSC change the tumour stroma and alter the secretion of extracellular matrix components in pancreatic cancer. It should be noted that MDSC have been shown to change the extracellular matrix and support metastasis formation in different animal models. Future studies are clearly indicated to decipher the exact mechanism of how specifically granulocytic MDSC modulate the stroma in pancreatic cancer and increase vessel patency in pancreatic cancer. Third, this study describes a novel mechanism of how immunotherapy may improve outcome, mainly by changing the extracelluar matrix in pancreatic cancer, an approach that has recently gained a lot of attention in a number of preclinical tumour settings.11 But one important question remains: How can we translate these findings into the clinic? Gemcitabine, a chemotherapeutic reagent frequently used to treat patients with pancreatic cancer, has been shown to target MDSC and improve immune responses in a mouse model of breast cancer.12 While an increased frequency of MDSC has been reported in patients with pancreatic cancer, it remains unclear which MDSC subset dominates. It is not clear whether gemcitabine will selectively target granulocytic MDSC, and, indeed, conflicting data are available on the effect of gemcitabine treatment on MDSC in patients with pancreatic cancer. While one study failed to demonstrate any clear effect on MDSC frequencies in patients with advanced pancreatic cancer treated with gemcitabine plus capecitabine,13 another study in pancreatic cancer patients treated with gemcitabine in combination with a synthetic triterpenoid resulted in improved T cell function caused by impaired MDSC function without affecting MDSC numbers.14 Ultimately it is hard to believe that any type of MDSC targeting monotherapy will be potent enough to result in clinically meaningful responses. Gut November 2014 Vol 63 No 11
Downloaded from http://gut.bmj.com/ on January 20, 2015 - Published by group.bmj.com
Commentary Future studies are required to study novel approaches combining the targeting of MDSC with other immune interventions in order to enhance antitumour immunity or chemotherapeutic drug delivery. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
REFERENCES 1 2
3
4
5
To cite Greten TF. Gut 2014;63:1690–1691.
6
Received 25 February 2014 Accepted 26 February 2014 Published Online First 14 March 2014 7
▸ http://dx.doi.org/10.1136/gutjnl-2013-306271 Gut 2014;63:1690–1691. doi:10.1136/gutjnl-2014-306790
Gut November 2014 Vol 63 No 11
8
Talmadge JE, Gabrilovich D. History of myeloid-derived suppressor cells. Nat Rev Cancer 2013;13:7752. Greten TF, Manns MP, Korangy F. Myeloid derived suppressor cells in human diseases. Int Immunopharmacol 2011;11:802–7. Youn J-I, Nagaraj S, Collazo M, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 2008;181:5791–802. Zhao F, Obermann S, Wasielewski von R, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 2009;128:141–9. Clark CE, Hingorani SR, Mick R, et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:9518–27. Bayne LJ, Beatty GL, Jhala N, et al. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer. Cancer Cell 2012;21:822–35. Pylayeva-Gupta Y, Lee KE, Hajdu CH, et al. Oncogenic Kras-Induced GM-CSF Production Promotes the Development of Pancreatic Neoplasia. Cancer Cell 2012;21:836–47. Porembka MR, Mitchem JB, Belt BA, et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012;61:1373–85.
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Duffy A, Zhao F, Haile L, et al. Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies. Cancer Immunol Immunother 2013;62:299–307. Stromnes IM, Brockenbrough JS, Izeradjene K, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 2014;63:1728–36. Kerkar SP, Restifo NP. Cellular Constituents of Immune Escape within the Tumor Microenvironment. Cancer Res 2012;72:3125–30. Le HK, Graham L, Cha E, et al. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumorbearing mice. Int Immunopharmacol 2009;9: 900–9. Annels NE, Shaw VE, Gabitass RF, et al. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunol Immunother 2013;63:175–83. Nagaraj S, Youn J-I, Weber H, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 2010;16:1812–23.
1691
Downloaded from http://gut.bmj.com/ on January 20, 2015 - Published by group.bmj.com
Myeloid-derived suppressor cells in pancreatic cancer: more than a hidden barrier for antitumour immunity? Tim F Greten Gut 2014 63: 1690-1691 originally published online March 14, 2014
doi: 10.1136/gutjnl-2014-306790 Updated information and services can be found at: http://gut.bmj.com/content/63/11/1690
These include:
References Email alerting service
This article cites 13 articles, 3 of which you can access for free at: http://gut.bmj.com/content/63/11/1690#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Commentary
Myeloid-derived suppressor cells in pancreatic cancer: more than a hidden barrier for antitumour immunity? Tim F Greten Myeloid-derived suppressor cells (MDSC) represent an immune cell subset with profound immune suppressor function. Initially described in 1978 as natural suppressor cells, this cell type has gained significant attention in recent years not only among tumour immunologists but also among medical oncologists interested both in developing new immune-based antitumour strategies and trying to understand how conventional non-immunological therapies affect antitumour immune responses.1 MDSC represent a mixture of immature cell types that accumulate in tumour-bearing mice and patients with cancer. Tumour-derived factors block the maturation of myeloid cells at different stages, leading to accumulation of these cells in tumours, as well as in the periphery. At least two different subsets of MDSC have been described in mice and men: monocytic and polymorphonuclear granulocytic MDSC, which can be identified as CD14+HLA-DRlo/neg and neg + lin CD11b HLA-DRneg in patients2 and as CD11b+Ly6G+ Ly6Clow or + neg hi CD11b Ly6G Ly6C in mice.3 An accumulation of MDSC has been described in multiple models of pancreatic cancer. We have been able to demonstrate an accumulation of MDSC in mice with premalignant lesions.4 Similarly, an accumulation of MDSC, regulatory T cells and tumour-associated macrophages has been described in KC mice, which express the KrasG12D allele under the pancreaticspecific promoter Pdx-1,5 suggesting that accumulation of MDSC is an early event during pancreatic cancer development. Oncogenic K-ras-induced GM-CSF production by pancreatic ductal epithelial cells, which can also be detected in human PanIn lesions, is required for the recruitment of CD11b+Gr1+ cells.6 7 Analysis of MDSC in peripheral blood from patients with pancreatic cancer8 9 corroborated findings obtained in different murine pancreatic cancer models and further stressed Correspondence to Professor Tim F Greten, Thoracic and Gastrointestinal Oncology Branch, Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; [email protected] 1690
the potential importance of this cell type in pancreatic cancer. Using genetically engineered mice, which express KrasG12D and mutatedTrp53 in the pancreas (KPC mice) and develop autochthonous pancreatic ductal adenocarcinoma, Dr Hingorani’s group went one step further and studied the function of specific MDSC subsets in pancreatic cancer both in vitro and in vivo.10 The authors observed a specific increase in the frequency of granulocytic CD11b+Gr-1highLy6cint MDSC from preinvasive to invasive pancreatic adenocarcinoma, suggesting that accumulation of granulocytic MDSC is a late event during tumour development. These granulocytic MDSC were not only potent T cell suppressors but were also more potent at inducing T cell apoptosis than their counterparts from spleen or bone marrow. Survival of granulocytic MDSC was dependent on GM-CSF released by tumour cells, corroborating previous studies that had already demonstrated a pivotal role for this cytokine in MDSC generation in mice with pancreatic cancer.6 7 Probably the most important results came from experiments in which the authors selectively depleted granulocytic MDSC in mice with invasive pancreatic adenocarcinoma. Interestingly, depletion of granulocytic MDSC led to fourfold to fivefold increase of monocytic MDSC, suggesting a homeostatic relationship between the two subsets. At first glance, it may have been disappointing to notice that depletion of granulocytic MDSC did not change tumour masses in treated mice but rather these tumours grew instead. It is not clear whether more time was needed so that activation of T cells can actually induce tumour responses. However, this tumour growth was accompanied by an influx of proliferating, activated, granzyme B+ CD8+ T cells in tumours, suggesting that depletion of granulocytic MDSC enhanced CD8-mediated antitumour immunity in mice with pancreatic adenocarcinoma. Some indications of a functional relevance for these findings came from the observation that depletion of granulocytic MDSC affected the stromal architecture and integrity of tumours. Increased apoptosis of tumour epithelial cells along with decreased extracellular
matrix deposition and the appearance of patent blood vessels were observed in treated mice. These studies have important implications for the field of those working on immunotherapy in general as well as those trying to develop better treatments for patients with pancreatic cancer. The authors very nicely demonstrated that premature conclusions should be avoided from the plain observation of tumour growth in immunotherapy settings. Thorough analysis of the primary tumour site revealed some novel and interesting insights on MDSC biology. First, granulocytic MDSC induced apoptosis in T cells, suggesting a previously unrecognised mode of suppressor function. Second, the authors describe a novel mechanism of how granulocytic MDSC change the tumour stroma and alter the secretion of extracellular matrix components in pancreatic cancer. It should be noted that MDSC have been shown to change the extracellular matrix and support metastasis formation in different animal models. Future studies are clearly indicated to decipher the exact mechanism of how specifically granulocytic MDSC modulate the stroma in pancreatic cancer and increase vessel patency in pancreatic cancer. Third, this study describes a novel mechanism of how immunotherapy may improve outcome, mainly by changing the extracelluar matrix in pancreatic cancer, an approach that has recently gained a lot of attention in a number of preclinical tumour settings.11 But one important question remains: How can we translate these findings into the clinic? Gemcitabine, a chemotherapeutic reagent frequently used to treat patients with pancreatic cancer, has been shown to target MDSC and improve immune responses in a mouse model of breast cancer.12 While an increased frequency of MDSC has been reported in patients with pancreatic cancer, it remains unclear which MDSC subset dominates. It is not clear whether gemcitabine will selectively target granulocytic MDSC, and, indeed, conflicting data are available on the effect of gemcitabine treatment on MDSC in patients with pancreatic cancer. While one study failed to demonstrate any clear effect on MDSC frequencies in patients with advanced pancreatic cancer treated with gemcitabine plus capecitabine,13 another study in pancreatic cancer patients treated with gemcitabine in combination with a synthetic triterpenoid resulted in improved T cell function caused by impaired MDSC function without affecting MDSC numbers.14 Ultimately it is hard to believe that any type of MDSC targeting monotherapy will be potent enough to result in clinically meaningful responses. Gut November 2014 Vol 63 No 11
Downloaded from http://gut.bmj.com/ on January 20, 2015 - Published by group.bmj.com
Commentary Future studies are required to study novel approaches combining the targeting of MDSC with other immune interventions in order to enhance antitumour immunity or chemotherapeutic drug delivery. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
REFERENCES 1 2
3
4
5
To cite Greten TF. Gut 2014;63:1690–1691.
6
Received 25 February 2014 Accepted 26 February 2014 Published Online First 14 March 2014 7
▸ http://dx.doi.org/10.1136/gutjnl-2013-306271 Gut 2014;63:1690–1691. doi:10.1136/gutjnl-2014-306790
Gut November 2014 Vol 63 No 11
8
Talmadge JE, Gabrilovich D. History of myeloid-derived suppressor cells. Nat Rev Cancer 2013;13:7752. Greten TF, Manns MP, Korangy F. Myeloid derived suppressor cells in human diseases. Int Immunopharmacol 2011;11:802–7. Youn J-I, Nagaraj S, Collazo M, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 2008;181:5791–802. Zhao F, Obermann S, Wasielewski von R, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 2009;128:141–9. Clark CE, Hingorani SR, Mick R, et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:9518–27. Bayne LJ, Beatty GL, Jhala N, et al. Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer. Cancer Cell 2012;21:822–35. Pylayeva-Gupta Y, Lee KE, Hajdu CH, et al. Oncogenic Kras-Induced GM-CSF Production Promotes the Development of Pancreatic Neoplasia. Cancer Cell 2012;21:836–47. Porembka MR, Mitchem JB, Belt BA, et al. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 2012;61:1373–85.
9
10
11
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13
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Duffy A, Zhao F, Haile L, et al. Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies. Cancer Immunol Immunother 2013;62:299–307. Stromnes IM, Brockenbrough JS, Izeradjene K, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 2014;63:1728–36. Kerkar SP, Restifo NP. Cellular Constituents of Immune Escape within the Tumor Microenvironment. Cancer Res 2012;72:3125–30. Le HK, Graham L, Cha E, et al. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumorbearing mice. Int Immunopharmacol 2009;9: 900–9. Annels NE, Shaw VE, Gabitass RF, et al. The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer. Cancer Immunol Immunother 2013;63:175–83. Nagaraj S, Youn J-I, Weber H, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 2010;16:1812–23.
1691
Downloaded from http://gut.bmj.com/ on January 20, 2015 - Published by group.bmj.com
Myeloid-derived suppressor cells in pancreatic cancer: more than a hidden barrier for antitumour immunity? Tim F Greten Gut 2014 63: 1690-1691 originally published online March 14, 2014
doi: 10.1136/gutjnl-2014-306790 Updated information and services can be found at: http://gut.bmj.com/content/63/11/1690
These include:
References Email alerting service
This article cites 13 articles, 3 of which you can access for free at: http://gut.bmj.com/content/63/11/1690#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
