Abstract | PURPOSE: 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-Ƴ and CXCL10 but had no significant effect on the expression of IL-6 or TGF-β. Concurrent administration of veliparib and subablative radiation therapy (8 Gy × 2) significantly prolonged anti-PD-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 veliparib and IR was attenuated by CD8+ T-cell depletion. CONCLUSIONS:
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Authors | Steven N Seyedin, M M Hasibuzzaman, Vivan Pham, Michael S Petronek, Cameron Callaghan, Amanda L Kalen, Kranti A Mapuskar, Sarah L Mott, Douglas R Spitz, Bryan G Allen, Joseph M Caster |
Journal | International journal of radiation oncology, biology, physics
(Int J Radiat Oncol Biol Phys)
Vol. 108
Issue 1
Pg. 81-92
(09 01 2020)
ISSN: 1879-355X [Electronic] United States |
PMID | 32036006
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2020 Elsevier Inc. All rights reserved. |
Chemical References |
- Benzimidazoles
- Poly(ADP-ribose) Polymerase Inhibitors
- Radiation-Sensitizing Agents
- veliparib
- Poly(ADP-ribose) Polymerases
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Topics |
- Animals
- Antigen Presentation
(drug effects)
- Benzimidazoles
(pharmacology, therapeutic use)
- Cell Transformation, Neoplastic
- Colorectal Neoplasms
(drug therapy, immunology, pathology, radiotherapy)
- Combined Modality Therapy
- Female
- Humans
- Male
- Mice
- Poly(ADP-ribose) Polymerase Inhibitors
(pharmacology, therapeutic use)
- Poly(ADP-ribose) Polymerases
(metabolism)
- Radiation-Sensitizing Agents
(pharmacology, therapeutic use)
- Treatment Outcome
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