Journal article
Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models
International journal of radiation oncology, biology, physics, Vol.108(1), pp.81-92
09/01/2020
DOI: 10.1016/j.ijrobp.2020.01.030
PMCID: PMC7416439
PMID: 32036006
Abstract
Purpose: The majority of colorectal cancers are resistant to cancer immune checkpoint inhibitors. Ionizing radiation (IR) and several radiosensitizers, including PARP inhibitors, can enhance responsiveness to immune checkpoint inhibitors by potentially complementary mechanisms of action. We assessed the ability of radiation and PARP inhibition to induce proimmunogenic changes in tumor cells and enhance their in vivo responsiveness to anti-PD-1 antibodies.
Methods and Materials: We performed a candidate drug screen and used flow cytometry to assess effects of the PARP inhibitor veliparib on IR-mediated changes in MHC-1 antigen presentation and surface localization of immune-modulating proteins including PD-L1 and calreticulin in colorectal cancer tumor models. Reverse transcription polymerase chain reaction was used to assess the effects of veliparib and radiation on the expression of proinflammatory and immunosuppressive cytokines. The ability of concurrent PARP inhibition and subablative doses of radiation therapy to enhance in vivo responsiveness to anti-PD-1 antibodies was assessed using unilateral flank-tumor models with or without T-cell depletion.
Results: Veliparib was a potent radiosensitizer in both cell lines. Radiation increased surface localization of MHC-1 and PD-L1 in a dose-dependent manner, and veliparib pretreatment significantly enhanced these effects with high (8 Gy) but not with lower radiation doses. Enhancement of MHC-1 and PD-L1 surface localization by IR and IR+ veliparib remained significant 1, 3, and 7 days after treatment. IR significantly increased delayed tumoral expression of proinflammatory cytokines interferon-gamma and CXCL10 but had no significant effect on the expression of IL-6 or TGF-beta. Concurrent administration of veliparib and subablative radiation therapy (8 Gy x 2) significantly prolonged antiPD-1-mediated in vivo tumor growth delay and survival in both tumor models. Moreover, these effects were more pronounced in the microsatellite instability-mutated MC38 tumor model. Enhancement of anti-PD-1 mediated tumor growth delay with yeliparib and IR was attenuated by CD8+ T-cell depletion.
Conclusions: We provide preclinical evidence for a novel therapeutic strategy to enhance responsiveness of colorectal tumors to immune checkpoint inhibitors. (C) 2020 Elsevier Inc. All rights reserved.
Details
- Title: Subtitle
- Combination Therapy with Radiation and PARP Inhibition Enhances Responsiveness to Anti-PD-1 Therapy in Colorectal Tumor Models
- Creators
- Steven N. Seyedin - University of IowaM. M. Hasibuzzaman - University of IowaVivan Pham - Roy J. and Lucille A. Carver College of MedicineMichael S. Petronek - University of IowaCameron Callaghan - University of IowaAmanda L. Kalen - University of IowaKranti A. Mapuskar - University of IowaSarah L. Mott - University of IowaDouglas R. Spitz - University of Iowa Hospitals and ClinicsBryan G. Allen - University of Iowa Hospitals and ClinicsJoseph M. Caster - University of Iowa Hospitals and Clinics
- Resource Type
- Journal article
- Publication Details
- International journal of radiation oncology, biology, physics, Vol.108(1), pp.81-92
- DOI
- 10.1016/j.ijrobp.2020.01.030
- PMID
- 32036006
- PMCID
- PMC7416439
- NLM abbreviation
- Int J Radiat Oncol Biol Phys
- ISSN
- 0360-3016
- eISSN
- 1879-355X
- Publisher
- Elsevier
- Number of pages
- 12
- Grant note
- Carver College of Medicine Iowa City Veterans Administration Medical Center P30CA086862 / Holden Comprehensive Cancer Center (National Cancer Institute of the National Institutes of Health) University of Iowa Carver College of Medicine P30CA086862 / National Cancer Institute of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Holden Comprehensive Cancer Center
- Language
- English
- Date published
- 09/01/2020
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Orthopedics and Rehabilitation; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984312965202771
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