Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

Samarth Hegde; Varintra E. Krisnawan; Brett H. Herzog; Chong Zuo; Marcus A. Breden; Brett L. Knolhoff; Graham D. Hogg; Jack P. Tang; John M. Baer; Cedric Mpoy; Kyung Bae Lee; Katherine A. Alexander; Buck E. Rogers; Kenneth M. Murphy; William G. Hawkins; Ryan C. Fields; Carl J. DeSelm; Julie K. Schwarz; David G. DeNardo

doi:10.1016/j.ccell.2020.02.008

Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

Samarth Hegde, Varintra E. Krisnawan, Brett H. Herzog, Chong Zuo, Marcus A. Breden, Brett L. Knolhoff, Graham D. Hogg, Jack P. Tang, John M. Baer, Cedric Mpoy, Kyung Bae Lee, Katherine A. Alexander, Buck E. Rogers, Kenneth M. Murphy, William G. Hawkins, Ryan C. Fields, Carl J. DeSelm, Julie K. Schwarz, David G. DeNardo

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307 Scopus citations

Abstract

Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic T_H17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.

Original language	English
Pages (from-to)	289-307.e9
Journal	Cancer Cell
Volume	37
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2020.02.008
State	Published - Mar 16 2020

Keywords

CD40
Flt3L
dendritic cell
immune surveillance
immunotherapy
neoantigen
pancreatic cancer
radiation therapy
vaccination

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10.1016/j.ccell.2020.02.008

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Hegde, S., Krisnawan, V. E., Herzog, B. H., Zuo, C., Breden, M. A., Knolhoff, B. L., Hogg, G. D., Tang, J. P., Baer, J. M., Mpoy, C., Lee, K. B., Alexander, K. A., Rogers, B. E., Murphy, K. M., Hawkins, W. G., Fields, R. C., DeSelm, C. J., Schwarz, J. K., & DeNardo, D. G. (2020). Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer. Cancer Cell, 37(3), 289-307.e9. https://doi.org/10.1016/j.ccell.2020.02.008

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title = "Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer",

abstract = "Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.",

keywords = "CD40, Flt3L, dendritic cell, immune surveillance, immunotherapy, neoantigen, pancreatic cancer, radiation therapy, vaccination",

author = "Samarth Hegde and Krisnawan, {Varintra E.} and Herzog, {Brett H.} and Chong Zuo and Breden, {Marcus A.} and Knolhoff, {Brett L.} and Hogg, {Graham D.} and Tang, {Jack P.} and Baer, {John M.} and Cedric Mpoy and Lee, {Kyung Bae} and Alexander, {Katherine A.} and Rogers, {Buck E.} and Murphy, {Kenneth M.} and Hawkins, {William G.} and Fields, {Ryan C.} and DeSelm, {Carl J.} and Schwarz, {Julie K.} and DeNardo, {David G.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = mar,

day = "16",

doi = "10.1016/j.ccell.2020.02.008",

language = "English",

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Hegde, S, Krisnawan, VE, Herzog, BH, Zuo, C, Breden, MA, Knolhoff, BL, Hogg, GD, Tang, JP, Baer, JM, Mpoy, C, Lee, KB, Alexander, KA, Rogers, BE , Murphy, KM, Hawkins, WG, Fields, RC , DeSelm, CJ , Schwarz, JK & DeNardo, DG 2020, 'Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer', Cancer Cell, vol. 37, no. 3, pp. 289-307.e9. https://doi.org/10.1016/j.ccell.2020.02.008

TY - JOUR

T1 - Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

AU - Hegde, Samarth

AU - Krisnawan, Varintra E.

AU - Herzog, Brett H.

AU - Zuo, Chong

AU - Breden, Marcus A.

AU - Knolhoff, Brett L.

AU - Hogg, Graham D.

AU - Tang, Jack P.

AU - Baer, John M.

AU - Mpoy, Cedric

AU - Lee, Kyung Bae

AU - Alexander, Katherine A.

AU - Rogers, Buck E.

AU - Murphy, Kenneth M.

AU - Hawkins, William G.

AU - Fields, Ryan C.

AU - DeSelm, Carl J.

AU - Schwarz, Julie K.

AU - DeNardo, David G.

PY - 2020/3/16

Y1 - 2020/3/16

N2 - Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.

AB - Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.

KW - CD40

KW - Flt3L

KW - dendritic cell

KW - immune surveillance

KW - immunotherapy

KW - neoantigen

KW - pancreatic cancer

KW - radiation therapy

KW - vaccination

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AN - SCOPUS:85081203651

SN - 1535-6108

VL - 37

SP - 289-307.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer

Abstract

Keywords

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