Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model.
Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor "priming". Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft). We found that a single dose of Apo2L/TRAIL resulted in a wave of apoptosis which reached a maximum at 8h post-treatment. Apoptotic debris subsequently disappeared concurrent with an increase in macrophage infiltration. By 24h post-treatment, treated tumors appeared less condensed with widening of the stromal areas which increased at 48 and 72h. Analysis of tumor vasculature demonstrated a significant increase in overall vessel size at 48 and 72h although the number of vessels did not change. Notably, IFP was significantly reduced in these tumors by 48h after Apo2L/TRAIL treatment. Administration of gemcitabine at this time resulted in increased tumor uptake of both gemcitabine and liposomal gemcitabine and significantly improved anti-tumor efficacy of liposomal gemcitabine. These results suggest that Apo2L/TRAIL has a potential as a tumor priming agent and provides a rationale for developing a sequencing schema for combination therapy such that an initial dose of Apo2L/TRAIL would precede administration of gemcitabine or other therapies.
Dept. of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address: Bonnie.Hylander@roswellpark.org.
Bonnie L
BL
Hylander
Dept. of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Arindam
A
Sen
Dept. of Cell Stress, Roswell Park Cancer Institute, Buffalo, NY, USA.
Sarah H
SH
Beachy
Dept. of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Rose
R
Pitoniak
Dept. of Cell Stress, Roswell Park Cancer Institute, Buffalo, NY, USA.
Soumya
S
Ullas
Dept. of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
John F
JF
Gibbs
Dept. of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Jingxin
J
Qiu
Dept. of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Joshua D
JD
Prey
Dept. of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Gerald J
GJ
Fetterly
Dept. of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address: Elizabeth.Repasky@roswellpark.org.
Elizabeth A
EA
Repasky
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D045604:Extracellular Fluid / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008081:Liposomes; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D053221:TNF-Related Apoptosis-Inducing Ligand; D003841:Deoxycytidine; D000093542:Gemcitabine
Apo2L/TRAIL; Drug uptake; Gemcitabine; Interstitial fluid pressure; Liposomes; Patient tumor xenograft