Reference SummaryDixit A, JCI Insight 2022 Nov 22;7(22):

Title

 Targeting TNF-alpha-producing macrophages activates antitumor immunity in pancreatic cancer via IL-33 signaling.

Authors

 Dixit A; Sarver A; Zettervall J; Huang H; Zheng K; Brekken RA; Provenzano PP

Journal

 JCI Insight

Volume

 7

Issue

 22

Year

 2022

Pages

Abstract

 Pancreatic ductal adenocarcinoma (PDA) remains resistant to immune therapies, largely owing to robustly fibrotic and immunosuppressive tumor microenvironments. It has been postulated that excessive accumulation of immunosuppressive myeloid cells influences immunotherapy resistance, and recent studies targeting macrophages in combination with checkpoint blockade have demonstrated promising preclinical results. Yet our understanding of tumor-associated macrophage (TAM) function, complexity, and diversity in PDA remains limited. Our analysis reveals significant macrophage heterogeneity, with bone marrow-derived monocytes serving as the primary source for immunosuppressive TAMs. These cells also serve as a primary source of TNF-alpha, which suppresses expression of the alarmin IL-33 in carcinoma cells. Deletion of Ccr2 in genetically engineered mice decreased monocyte recruitment, resulting in profoundly decreased TNF-alpha and increased IL-33 expression, decreased metastasis, and increased survival. Moreover, intervention studies targeting CCR2 with a new orthosteric inhibitor (CCX598) rendered PDA susceptible to checkpoint blockade, resulting in reduced metastatic burden and increased survival. Our data indicate that this shift in antitumor immunity is influenced by increased levels of IL-33, which increases dendritic cell and cytotoxic T cell activity. These data demonstrate that interventions to disrupt infiltration of immunosuppressive macrophages, or their signaling, have the potential to overcome barriers to effective immunotherapeutics for PDA.

Links

 J:332123 – MGI References
36256464 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • gemcitabine
 Pancreas

100
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Pancreas

100
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • CCR2 inhibitor (CCX598)
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Pancreas

100
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Abdominal wall

0
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • anti-CTLA4 antibody
 Liver

41.67
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • CCR2 inhibitor (CCX598)
  • gemcitabine
  • anti-PD1 antibody
 Liver

41.67
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • CCR2 inhibitor (CCX598)
  • anti-CTLA4 antibody
  • anti-PD1 antibody
 Lung

25
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • gemcitabine
 Lung

25
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • CCR2 inhibitor (CCX598)
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Abdominal wall

8
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • anti-PD1 antibody
 Liver

55
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • anti-CTLA4 antibody
  • gemcitabine
 Liver

55
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - ductal
  • CCR2 inhibitor (CCX598)
  • gemcitabine
  • anti-PD1 antibody
 Lung

11
B6;FVB-Cdkn2atm4Rdp Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Pancreas adenocarcinoma - ductal Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - moderately differentiated Pancreas

observed
SHN Pancreas adenocarcinoma - moderately differentiated Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - poorly differentiated Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - poorly differentiated Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - well-differentiated Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas adenocarcinoma - well-differentiated Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas carcinoma
  • gemcitabine
 Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas carcinoma
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas carcinoma
  • CCR2 inhibitor (CCX598)
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas carcinoma Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas carcinoma
  • CCR2 inhibitor (CCX598)
  • anti-CTLA4 antibody
  • gemcitabine
  • anti-PD1 antibody
 Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas pancreatic intraepithelial neoplasia (PanIN) Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas pancreatic intraepithelial neoplasia (PanIN) Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas pancreatic intraepithelial neoplasia (PanIN) - high grade Pancreas

observed
SHN Pancreas pancreatic intraepithelial neoplasia (PanIN) - high grade Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas pancreatic intraepithelial neoplasia (PanIN) - low grade Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas pancreatic intraepithelial neoplasia (PanIN) - low grade Pancreas

observed
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Pancreas

observed - 86
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Pancreas

observed
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor (Unspecified organ)

40
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Liver

55
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Lung

41
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Muscle - Striated - Skeletal - Diaphragm

37
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Lymph node

77
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Spleen

14 - 55
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Gallbladder

23
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Abdominal wall

5
C57BL/6-Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Intestine

23
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Liver

26
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Lung

32
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Muscle - Striated - Skeletal - Diaphragm

21
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Lymph node

79
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Spleen

5 - 41
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Abdominal wall

0
C57BL/6-Ccr2tm1Ifc Krastm4Tyj/+ Tg(Pdx1-cre)6Tuv Trp53tm2Tyj/+ Pancreas tumor Intestine

21
B6;FVB-Cdkn2atm4Rdp Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Pancreas tumor Pancreas

observed