PD‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) is considered a non‐immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregu...

Full description

Saved in:
Bibliographic Details
Published in:EMBO molecular medicine 2017-02, Vol.9 (2), p.167-180
Main Authors: Azad, Abul, Yin Lim, Su, D'Costa, Zenobia, Jones, Keaton, Diana, Angela, Sansom, Owen J, Kruger, Philipp, Liu, Stanley, McKenna, W Gillies, Dushek, Omer, Muschel, Ruth J, Fokas, Emmanouil
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - drug therapy
Adenocarcinoma - radiotherapy
Allografts
Animals
B7-H1 Antigen - antagonists & inhibitors
Cancer therapies
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - radiotherapy
CD11b antigen
CD44 antigen
CD45 antigen
CD69 antigen
CD8 antigen
CD8-Positive T-Lymphocytes
Cell activation
Chemotherapy
Cytotoxicity
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Disease Models, Animal
FasL protein
Flow cytometry
Gemcitabine
Immune checkpoint inhibitors
Immune system
Immunogenicity
Immunotherapy
Kinases
liver metastases
Lymphocytes T
mathematical modeling
Mathematical models
Medical prognosis
Metastases
Metastasis
Mice
Models, Theoretical
Pancreas
Pancreatic cancer
PD-L1 protein
PD‐L1 immune checkpoint
Radiation therapy
Radiation-Sensitizing Agents - administration & dosage
Radiosensitization
Stat1 protein
Treatment Outcome
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Pancreatic ductal adenocarcinoma (PDAC) is considered a non‐immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD‐L1 expression in a JAK/Stat1‐dependent manner. In vitro, PD‐L1 inhibition did not alter radio‐ and chemosensitivity. In vivo, addition of anti‐PD‐L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD‐L1 blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced CD45+CD8+ T‐cell infiltration with concomitant upregulation of T‐cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radiosensitization by anti‐PD‐L1. Blockade of PD‐L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti‐PD‐L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC. Synopsis Local recurrence is a major cause of morbidity and mortality in pancreatic ductal adenocarcinoma (PDAC). Here, radiotherapy (RT) and gemcitabine chemotherapy are shown to have substantial immunomodulatory effects, including upregulation of PD‐L1. RT and gemcitabine chemotherapy induce PD‐L1 upregulation mediated by Jak/Stat1 signaling in PDAC cells. PD‐L1 blockade enhances primary tumor response to high‐dose RT and chemoradiotherapy and decreases formation of liver metastases in PDAC. Combination of RT and PD‐L1 blockade promotes infiltration and activation of cytotoxic T cells but decreases myeloid and Treg cell numbers. Mathematical modelling can provide an explanation of the complementary role of RT with PD‐L1 inhibition in PDAC. Local recurrence is a major cause of morbidity and mortality in pancreatic ductal adenocarcinoma (PDAC). Here, radiotherapy (RT) and gemcitabine chemotherapy are shown to have substantial immunomodulatory effects, including upregulation of PD‐L1.
ISSN:1757-4676
1757-4684
DOI:10.15252/emmm.201606674