TY - JOUR
T1 - Dissecting the stromal signalingandregulation of myeloid cells and memory effector T cells in pancreatic cancer
AU - Blair, Alex B.
AU - Kim, Victoria M.
AU - Muth, Stephen T.
AU - Saung, May Tun
AU - Lokker, Nathalie
AU - Blouw, Barbara
AU - Armstrong, Todd D.
AU - Jaffee, Elizabeth M.
AU - Tsujikawa, Takahiro
AU - Coussens, Lisa M.
AU - He, Jin
AU - Burkhart, Richard A.
AU - Wolfgang, Christopher L.
AU - Zheng, Lei
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Purpose: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. Experimental Design: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. Results:Targeting stroma by degradingHAwithPEGPH20 in combination with vaccine decreases CXCL12/CXCR4/ CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8+ T cells, respectively. This corresponds with increased CCR7+ effector memory T-cell infiltration, an increase in tumor-specific IFNg, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target. Conclusions: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
AB - Purpose: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. Experimental Design: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. Results:Targeting stroma by degradingHAwithPEGPH20 in combination with vaccine decreases CXCL12/CXCR4/ CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8+ T cells, respectively. This corresponds with increased CCR7+ effector memory T-cell infiltration, an increase in tumor-specific IFNg, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target. Conclusions: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
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U2 - 10.1158/1078-0432.CCR-18-4192
DO - 10.1158/1078-0432.CCR-18-4192
M3 - Article
C2 - 31186314
AN - SCOPUS:85071783360
SN - 1078-0432
VL - 25
SP - 5351
EP - 5363
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -