Myeloid Cell Mediated Immune Suppression in Pancreatic Cancer
2021; Elsevier BV; Volume: 12; Issue: 5 Linguagem: Inglês
10.1016/j.jcmgh.2021.07.006
ISSN2352-345X
AutoresSamantha B. Kemp, Marina Pasca di Magliano, Howard C. Crawford,
Tópico(s)Cancer Immunotherapy and Biomarkers
ResumoPancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly universally lethal malignancy. PDA is characterized by extensive infiltration of immunosuppressive myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells. Myeloid cells in the tumor microenvironment inhibit cytotoxic T-cell responses promoting carcinogenesis. Immune checkpoint therapy has not been effective in PDA, most likely because of this robust immune suppression, making it critical to elucidate mechanisms behind this phenomenon. Here, we review myeloid cell infiltration and cellular crosstalk in PDA progression and highlight current therapeutic approaches to target myeloid cell-driven immune suppression. Pancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly universally lethal malignancy. PDA is characterized by extensive infiltration of immunosuppressive myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells. Myeloid cells in the tumor microenvironment inhibit cytotoxic T-cell responses promoting carcinogenesis. Immune checkpoint therapy has not been effective in PDA, most likely because of this robust immune suppression, making it critical to elucidate mechanisms behind this phenomenon. Here, we review myeloid cell infiltration and cellular crosstalk in PDA progression and highlight current therapeutic approaches to target myeloid cell-driven immune suppression. SummaryThe immunosuppressive tumor microenvironment in pancreatic cancer is comprised in part by various myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). We discuss the role of TAMs and MDSCs in promoting immune suppression and highlight current myeloid targeted therapies. The immunosuppressive tumor microenvironment in pancreatic cancer is comprised in part by various myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). We discuss the role of TAMs and MDSCs in promoting immune suppression and highlight current myeloid targeted therapies. Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, with a 5-year survival rate of only 10%.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 7-30Crossref PubMed Scopus (7267) Google Scholar PDA is projected to become the second leading cause of cancer-related deaths by 2030.2Rahib L. Smith B.D. Aizenberg R. Rosenzweig A.B. Fleshman J.M. Matrisian L.M. 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In this review, we will describe the critical role myeloid cells play as mediators of immune suppression in PDA and highlight potential strategies to target these cells in the context of combination immunotherapy. In normal physiology, myeloid cells develop from hematopoietic stem cells in the bone marrow in a process called myelopoiesis.29Messmer M.N. Netherby C.S. Banik D. Abrams S.I. Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy.Cancer Immunol Immunother. 2015; 64: 1-13Crossref PubMed Scopus (65) Google Scholar Myeloid cells are defined as CD45+ CD11b+ cells but further differentiate into distinct populations: macrophages, granulocytes, mast cells, and dendritic cells, all components of the innate immune system. Macrophages within the tumor are referred to as tumor-associated macrophages (TAMs) and have distinct features compared with normal macrophages. Granulocytes can be further divided into eosinophils, basophils, and neutrophils. Within the TME, neutrophils and monocytes are often in an immature state referred to as immature myeloid cells/myeloid-derived suppressor cell (MDSC). In this review we will focus specifically on the role of TAMs and MDSCs in PDA progression (Figure 1). Within the PDA TME, macrophages are an abundant immune cell population.30Long K.B. Collier A.I. Beatty G.L. Macrophages: key orchestrators of a tumor microenvironment defined by therapeutic resistance.Mol Immunol. 2019; 110: 3-12Crossref PubMed Scopus (13) Google Scholar,31DeNardo D.G. Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy.Nat Rev Immunol. 2019; 19: 369-382Crossref PubMed Scopus (403) Google Scholar Macrophages derived from embryonic progenitors constitute the tissue-resident population; macrophages can also derive from infiltrating monocytes.32Wynn T.A. Chawla A. Pollard J.W. 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Alternative activation of macrophages.Nat Rev Immunol. 2003; 3: 23-35Crossref PubMed Scopus (4400) Google Scholar M2 macrophages lose their antigen presentation abilities and act to instead suppress the immune response through a variety of mechanisms. The M1/M2 classification is an oversimplification that is helpful for broad description but does not accurately describe the in vivo heterogeneity of TAMs. TAMs within the tumor are derived from either infiltrating monocytes or embryonically derived, tissue-resident macrophages.38Zhu Y. Herndon J.M. Sojka D.K. Kim K.W. Knolhoff B.L. Zuo C. Cullinan D.R. Luo J. Bearden A.R. Lavine K.J. Yokoyama W.M. Hawkins W.G. Fields R.C. Randolph G.J. DeNardo D.G. 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The colony-stimulating factor 1/colony-stimulating factor 1 receptor (CSF1/CSF1R) axis recruits and polarizes immunosuppressive TAMs. CSF1R is the major lineage regulator for all macrophage subsets.35Qian B.Z. Pollard J.W. Macrophage diversity enhances tumor progression and metastasis.Cell. 2010; 141: 39-51Abstract Full Text Full Text PDF PubMed Scopus (2846) Google Scholar PDA tumors are infiltrated by CSF1R+ macrophages.41Candido J.B. Morton J.P. Bailey P. Campbell A.D. Karim S.A. Jamieson T. Lapienyte L. Gopinathan A. Clark W. McGhee E.J. Wang J. Escorcio-Correia M. Zollinger R. Roshani R. Drew L. Rishi L. Arkell R. Evans T.R.J. Nixon C. Jodrell D.I. Wilkinson R.W. Biankin A.V. Barry S.T. Balkwill F.R. Sansom O.J. CSF1R(+) macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype.Cell Rep. 2018; 23: 1448-1460Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar,42Zhu Y. Knolhoff B.L. 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CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models.Cancer Res. 2014; 74: 5057-5069Crossref PubMed Scopus (629) Google Scholar suggesting that although single agent immunotherapy is not sufficient to reduce tumor burden, immune checkpoint blockade in combination with TAM modulating therapies can effectively reverse immune therapy resistance. The CCL2/CCR2 chemokine axis is critical for the genesis of TAMs. CCL2 produced by tumor cells recruits CCR2+ monocytes from the bone marrow to the circulation that then differentiate into TAMs after entering the tumor tissue.43Shi C. Pamer E.G. Monocyte recruitment during infection and inflammation.Nat Rev Immunol. 2011; 11: 762-774Crossref PubMed Scopus (1550) Google Scholar PDA patients with high levels of circulating monocytes have worse overall survival rates.20Sanford D.E. Belt B.A. Panni R.Z. Mayer A. Deshpande A.D. Carpenter D. Mitchem J.B. Plambeck-Suess S.M. Worley L.A. Goetz B.D. Wang-Gillam A. Eberlein T.J. Denardo D.G. Goedegebuure S.P. Linehan D.C. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis.Clin Cancer Res. 2013; 19: 3404-3415Crossref PubMed Scopus (297) Google Scholar Monocytes in circulation do not possess the same immunosuppressive abilities as TAMs, suggesting the cellular crosstalk in the TME is critical for this function.20Sanford D.E. Belt B.A. Panni R.Z. Mayer A. Deshpande A.D. Carpenter D. Mitchem J.B. Plambeck-Suess S.M. Worley L.A. Goetz B.D. Wang-Gillam A. Eberlein T.J. Denardo D.G. Goedegebuure S.P. Linehan D.C. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis.Clin Cancer Res. 2013; 19: 3404-3415Crossref PubMed Scopus (297) Google Scholar CCR2 blockade in mice results in retention of CCR2+ monocytes in the bone marrow, impairing tumor growth.20Sanford D.E. Belt B.A. Panni R.Z. Mayer A. Deshpande A.D. Carpenter D. Mitchem J.B. Plambeck-Suess S.M. Worley L.A. Goetz B.D. Wang-Gillam A. Eberlein T.J. Denardo D.G. Goedegebuure S.P. Linehan D.C. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis.Clin Cancer Res. 2013; 19: 3404-3415Crossref PubMed Scopus (297) Google Scholar CCR2 blockade in combination with gemcitabine further impairs tumor growth.20Sanford D.E. Belt B.A. Panni R.Z. Mayer A. Deshpande A.D. Carpenter D. Mitchem J.B. Plambeck-Suess S.M. Worley L.A. Goetz B.D. Wang-Gillam A. Eberlein T.J. Denardo D.G. Goedegebuure S.P. Linehan D.C. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis.Clin Cancer Res. 2013; 19: 3404-3415Crossref PubMed Scopus (297) Google Scholar Similarly, in a PDA clinical trial, patients with borderline resectable and locally advanced disease were treated with a combination of FOLFIRINOX and CCR2 antagonist (PF-04136309).44Nywening T.M. Wang-Gillam A. Sanford D.E. Belt B.A. Panni R.Z. Cusworth B.M. Toriola A.T. Nieman R.K. Worley L.A. Yano M. Fowler K.J. Lockhart A.C. Suresh R. Tan B.R. Lim K.H. Fields R.C. Strasberg S.M. Hawkins W.G. DeNardo D.G. Goedegebuure S.P. Linehan D.C. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.Lancet Oncol. 2016; 17: 651-662Abstract Full Text Full Text PDF PubMed Google Scholar After treatment, patients had reduced circulating CCR2+ monocytes and subsequently fewer TAMs in the tumor, as well as increased CD8+ T cells.44Nywening T.M. Wang-Gillam A. Sanford D.E. Belt B.A. Panni R.Z. Cusworth B.M. Toriola A.T. Nieman R.K. Worley L.A. Yano M. Fowler K.J. Lockhart A.C. Suresh R. Tan B.R. Lim K.H. Fields R.C. Strasberg S.M. Hawkins W.G. DeNardo D.G. Goedegebuure S.P. Linehan D.C. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.Lancet Oncol. 2016; 17: 651-662Abstract Full Text Full Text PDF PubMed Google Scholar However, a recent phase 1b trial evaluated PF-04136309 in combination with gemcitabine/nab-paclitaxel in patients with metastatic PDA.45Noel M. O'Reilly E.M. Wolpin B.M. Ryan D.P. Bullock A.J. Britten C.D. Linehan D.C. Belt B.A. Gamelin E.C. Ganguly B. Yin D. Joh T. Jacobs I.A. Taylor C.T. Lowery M.A. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma.Invest New Drugs. 2020; 38: 800-811Crossref PubMed Scopus (35) Google Scholar Unlike the previous phase 1b trial, this study did not show that PF-04136309 added additional benefit to the prescribed chemotherapy regimen.45Noel M. O'Reilly E.M. Wolpin B.M. Ryan D.P. Bullock A.J. Britten C.D. Linehan D.C. Belt B.A. Gamelin E.C. Ganguly B. Yin D. Joh T. Jacobs I.A. Taylor C.T. Lowery M.A. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma.Invest New Drugs. 2020; 38: 800-811Crossref PubMed Scopus (35) Google Scholar Furthermore, in the setting of metastatic PDA, CCR2 inhibition in combination with gemcitabine/nab-paclitaxel was not tolerable in patients.45Noel M. O'Reilly E.M. Wolpin B.M. Ryan D.P. Bullock A.J. Britten C.D. Linehan D.C. Belt B.A. Gamelin E.C. Ganguly B. Yin D. Joh T. Jacobs I.A. Taylor C.T. Lowery M.A. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma.Invest New Drugs. 2020; 38: 800-811Crossref PubMed Scopus (35) Google Scholar Taken together, these reports suggest that the benefit of CCR2 inhibition may be limited to locally advanced disease that does not extend to metastatic patients. In addition to an increase in macrophage frequency in PDA, a recent study used multiplex immunofluorescence to evaluate the spatial relationship of M1 and M2 macrophages in human PDA.46Vayrynen S
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