Ingunn M Stromnes1, J Scott Brockenbrough2, Kamel Izeradjene2, Markus A Carlson2, Carlos Cuevas3, Randi M Simmons2, Philip D Greenberg4, Sunil R Hingorani5. 1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Department of Immunology, University of Washington, Seattle, Washington, USA. 2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 3. Department of Radiology, University of Washington School of Medicine, Seattle, Washington, USA. 4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Department of Immunology, University of Washington, Seattle, Washington, USA Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA. 5. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Abstract
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response. OBJECTIVE: To investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape the progression of pancreas cancer. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC) in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response to engage and target tumour epithelial cells. METHODS: A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal features of human PDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and the biological outcomes determined. RESULTS: PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known to influence myelopoiesis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells. Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated CD8 T cells and apoptosis of tumour epithelial cells and also remodels the tumour stroma. CONCLUSIONS: Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumour cell survival and accumulation. Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND:Pancreatic ductal adenocarcinoma (PDA) is characterised by a robust desmoplasia, including the notable accumulation of immunosuppressive cells that shield neoplastic cells from immune detection. Immune evasion may be further enhanced if the malignant cells fail to express high levels of antigens that are sufficiently immunogenic to engender an effector T cell response. OBJECTIVE: To investigate the predominant subsets of immunosuppressive cancer-conditioned myeloid cells that chronicle and shape the progression of pancreas cancer. We show that selective depletion of one subset of myeloid-derived suppressor cells (MDSC) in an autochthonous, genetically engineered mouse model (GEMM) of PDA unmasks the ability of the adaptive immune response to engage and target tumour epithelial cells. METHODS: A combination of in vivo and in vitro studies were performed employing a GEMM that faithfully recapitulates the cardinal features of humanPDA. The predominant cancer-conditioned myeloid cell subpopulation was specifically targeted in vivo and the biological outcomes determined. RESULTS:PDA orchestrates the induction of distinct subsets of cancer-associated myeloid cells through the production of factors known to influence myelopoiesis. These immature myeloid cells inhibit the proliferation and induce apoptosis of activated T cells. Targeted depletion of granulocytic MDSC (Gr-MDSC) in autochthonous PDA increases the intratumoral accumulation of activated CD8 T cells and apoptosis of tumour epithelial cells and also remodels the tumour stroma. CONCLUSIONS: Neoplastic ductal cells of the pancreas induce distinct myeloid cell subsets that promote tumour cell survival and accumulation. Targeted depletion of a single myeloid subset, the Gr-MDSC, can unmask an endogenous T cell response, disclosing an unexpected latent immunity and invoking targeting of Gr-MDSC as a potential strategy to exploit for treating this highly lethal disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
Growth Factors; Immune Response; Pancreatic Cancer
Authors: Peter J Campbell; Shinichi Yachida; Laura J Mudie; Philip J Stephens; Erin D Pleasance; Lucy A Stebbings; Laura A Morsberger; Calli Latimer; Stuart McLaren; Meng-Lay Lin; David J McBride; Ignacio Varela; Serena A Nik-Zainal; Catherine Leroy; Mingming Jia; Andrew Menzies; Adam P Butler; Jon W Teague; Constance A Griffin; John Burton; Harold Swerdlow; Michael A Quail; Michael R Stratton; Christine Iacobuzio-Donahue; P Andrew Futreal Journal: Nature Date: 2010-10-28 Impact factor: 49.962
Authors: Richard E Royal; Catherine Levy; Keli Turner; Aarti Mathur; Marybeth Hughes; Udai S Kammula; Richard M Sherry; Suzanne L Topalian; James C Yang; Israel Lowy; Steven A Rosenberg Journal: J Immunother Date: 2010-10 Impact factor: 4.456
Authors: Sven Brandau; Sokratis Trellakis; Kirsten Bruderek; Dominik Schmaltz; Gabriele Steller; Motaz Elian; Henrik Suttmann; Marcus Schenck; Jürgen Welling; Peter Zabel; Stephan Lang Journal: J Leukoc Biol Date: 2010-11-24 Impact factor: 4.962
Authors: P Goedegebuure; J B Mitchem; M R Porembka; M C B Tan; B A Belt; A Wang-Gillam; W E Gillanders; W G Hawkins; D C Linehan Journal: Curr Cancer Drug Targets Date: 2011-07 Impact factor: 3.428
Authors: Jedd D Wolchok; Axel Hoos; Steven O'Day; Jeffrey S Weber; Omid Hamid; Celeste Lebbé; Michele Maio; Michael Binder; Oliver Bohnsack; Geoffrey Nichol; Rachel Humphrey; F Stephen Hodi Journal: Clin Cancer Res Date: 2009-11-24 Impact factor: 12.531
Authors: Kenneth P Olive; Michael A Jacobetz; Christian J Davidson; Aarthi Gopinathan; Dominick McIntyre; Davina Honess; Basetti Madhu; Mae A Goldgraben; Meredith E Caldwell; David Allard; Kristopher K Frese; Gina Denicola; Christine Feig; Chelsea Combs; Stephen P Winter; Heather Ireland-Zecchini; Stefanie Reichelt; William J Howat; Alex Chang; Mousumi Dhara; Lifu Wang; Felix Rückert; Robert Grützmann; Christian Pilarsky; Kamel Izeradjene; Sunil R Hingorani; Pearl Huang; Susan E Davies; William Plunkett; Merrill Egorin; Ralph H Hruban; Nigel Whitebread; Karen McGovern; Julian Adams; Christine Iacobuzio-Donahue; John Griffiths; David A Tuveson Journal: Science Date: 2009-05-21 Impact factor: 47.728
Authors: Michel DuPage; Ann F Cheung; Claire Mazumdar; Monte M Winslow; Roderick Bronson; Leah M Schmidt; Denise Crowley; Jianzhu Chen; Tyler Jacks Journal: Cancer Cell Date: 2011-01-18 Impact factor: 31.743
Authors: Michael W Pickup; Philip Owens; Agnieszka E Gorska; Anna Chytil; Fei Ye; Chanjuan Shi; Valerie M Weaver; Raghu Kalluri; Harold L Moses; Sergey V Novitskiy Journal: Cancer Immunol Res Date: 2017-08-03 Impact factor: 11.151
Authors: Kristen B Long; Graham Tooker; Evan Tooker; Santiago Lombo Luque; Jae W Lee; Xiaoqing Pan; Gregory L Beatty Journal: Mol Cancer Ther Date: 2017-06-13 Impact factor: 6.261
Authors: Justin A Kenkel; William W Tseng; Matthew G Davidson; Lorna L Tolentino; Okmi Choi; Nupur Bhattacharya; E Scott Seeley; Daniel A Winer; Nathan E Reticker-Flynn; Edgar G Engleman Journal: Cancer Res Date: 2017-06-13 Impact factor: 12.701
Authors: Joseph A Flores-Toro; Defang Luo; Adithya Gopinath; Matthew R Sarkisian; James J Campbell; Israel F Charo; Rajinder Singh; Thomas J Schall; Meenal Datta; Rakesh K Jain; Duane A Mitchell; Jeffrey K Harrison Journal: Proc Natl Acad Sci U S A Date: 2019-12-26 Impact factor: 11.205