Open AccessPD ‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy
Author(s) -
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
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606674
Subject(s) - radiation oncology , medicine , pancreatic ductal adenocarcinoma , oncology , library science , pancreatic cancer , radiation therapy , cancer , computer science
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 CD 11b + Gr1 + myeloid cell infiltration and enhanced CD 45 + CD 8 + T‐cell infiltration with concomitant upregulation of T‐cell activation markers including CD 69, CD 44, and FasL, and increased CD 8:Treg ratio. Depletion of CD 8 + 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 .