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

EMBO Mol Med. 2017 Feb;9(2):167-180. doi: 10.15252/emmm.201606674.

Abstract

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.

Keywords: PD‐L1 immune checkpoint; liver metastases; mathematical modeling; pancreatic cancer; radiosensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / radiotherapy*
  • Animals
  • B7-H1 Antigen / antagonists & inhibitors*
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / radiotherapy*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Disease Models, Animal
  • Mice
  • Models, Theoretical
  • Radiation-Sensitizing Agents / administration & dosage*
  • Treatment Outcome

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Radiation-Sensitizing Agents
  • Deoxycytidine
  • gemcitabine