Stromal
Modulation Reverses Primary Resistance to
Immune Checkpoint Blockade in Pancreatic Cancer
Version 2 2018-09-21, 18:34
Version 1 2018-09-20, 20:44
Posted on 2018-09-21 - 18:34
Pancreatic
ductal adenocarcinoma (PDAC) remains one of the most
difficult cancers to treat. It is refractory to most existing therapies,
including immunotherapies, due to the presence of an excessive desmoplastic
stroma, which restricts penetration of drugs and cytotoxic CD8+ T cells. Stromal modulation has shown promising results in
the enhancement of immune checkpoint blockade treatment in PDAC. We
demonstrate here effective stromal modulation by a polymeric micelle-based
nanoformulation to codeliver a sonic hedgehog inhibitor (cyclopamine,
abbreviated as CPA) and a cytotoxic chemotherapy drug (paclitaxel,
abbreviated as PTX). The formulation, M-CPA/PTX, modulated the PDAC
stroma by increasing the intratumoral vasculature density, which then
promoted the tumor infiltration by cytotoxic CD8+ T cells
without depletion of tumor-restraining α-smooth muscle action-positive
fibroblasts and type I collage in the stroma. The combination of M-CPA/PTX
and the PD-1 checkpoint blockade significantly prolonged animal survival
in an orthotopic murine PDAC model as well as a genetically engineered
mouse model of PDAC. The superior antitumor efficacy was mediated
by enhanced tumor infiltration of CD8+ T cells without
concomitant infiltration of suppressive regulatory T cells or myeloid-derived
suppressor cells and by the coordinated action of PTX and interferon-gamma.
Our results demonstrate that stroma-modulating nanoformulations are
a promising approach to potentiate immune checkpoint blockade therapy
of pancreatic cancer.
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Zhao, Jun; Xiao, Zhilan; Li, Tingting; Chen, Huiqin; Yuan, Ying; Wang, Y. Alan; et al. (2018). Stromal
Modulation Reverses Primary Resistance to
Immune Checkpoint Blockade in Pancreatic Cancer. ACS Publications. Collection. https://doi.org/10.1021/acsnano.8b02481
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AUTHORS (10)
JZ
Jun Zhao
ZX
Zhilan Xiao
TL
Tingting Li
HC
Huiqin Chen
YY
Ying Yuan
YW
Y. Alan Wang
CH
Cheng-Hui Hsiao
DC
Diana S-L. Chow
WW
Willem W. Overwijk
CL
Chun Li
KEYWORDS
CPAstromamyeloid-derived suppressor cellsnanoformulationStromal Modulation Reversesintratumoral vasculature densityPTXPancreatic Cancer Pancreatic ductal adenocarcinomacytotoxic CD 8cytotoxic chemotherapy drugImmune Checkpoint Blockadeorthotopic murine PDAC modelcheckpoint blockade treatmentmuscle action-positive fibroblastsM-CPAmodulationT cellstumor infiltrationcheckpoint blockade therapy