Cargando…

Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model

Local radiotherapy (RT) is important to manage metastatic triple-negative breast cancer (TNBC). Although RT primarily reduces cancer cells locally, this control can be enhanced by triggering the immune system via immunotherapy. RT and immunotherapy may lead to an improved systemic effect, known as t...

Descripción completa

Detalles Bibliográficos
Autores principales: Song, Haa-Na, Jin, Hana, Kim, Jung-Hoon, Ha, In-Bong, Kang, Ki-Mun, Choi, Hoon-Sik, Jeong, Ho-Jin, Kim, Min-Young, Kim, Hye-Jung, Jeong, Bae-Kwon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509046/
https://www.ncbi.nlm.nih.gov/pubmed/34638817
http://dx.doi.org/10.3390/ijms221910476
_version_ 1784582242524200960
author Song, Haa-Na
Jin, Hana
Kim, Jung-Hoon
Ha, In-Bong
Kang, Ki-Mun
Choi, Hoon-Sik
Jeong, Ho-Jin
Kim, Min-Young
Kim, Hye-Jung
Jeong, Bae-Kwon
author_facet Song, Haa-Na
Jin, Hana
Kim, Jung-Hoon
Ha, In-Bong
Kang, Ki-Mun
Choi, Hoon-Sik
Jeong, Ho-Jin
Kim, Min-Young
Kim, Hye-Jung
Jeong, Bae-Kwon
author_sort Song, Haa-Na
collection PubMed
description Local radiotherapy (RT) is important to manage metastatic triple-negative breast cancer (TNBC). Although RT primarily reduces cancer cells locally, this control can be enhanced by triggering the immune system via immunotherapy. RT and immunotherapy may lead to an improved systemic effect, known as the abscopal effect. Here, we analyzed the antitumor effect of combination therapy using RT with an anti-programmed cell death-1 (PD-1) antibody in primary tumors, using poorly immunogenic metastatic mouse mammary carcinoma 4T1 model. Mice were injected subcutaneously into both flanks with 4T1 cells, and treatment was initiated 12 days later. Mice were randomly assigned to three treatment groups: (1) control (no treatment with RT or immune checkpoint inhibitor (ICI)), (2) RT alone, and (3) RT+ICI. The same RT dose was prescribed in both RT-alone and RT+ICI groups as 10Gy/fx in two fractions and delivered to only one of the two tumor burdens injected at both sides of flanks. In the RT+ICI group, 200 µg fixed dose of PD-1 antibody was intraperitoneally administered concurrently with RT. The RT and ICI combination markedly reduced tumor cell growth not only in the irradiated site but also in non-irradiated sites, a typical characteristic of the abscopal effect. This was observed only in radiation-sensitive cancer cells. Lung metastasis development was lower in RT-irradiated groups (RT-only and RT+ICI groups) than in the non-irradiated group, regardless of the radiation sensitivity of tumor cells. However, there was no additive effect of ICI on RT to control lung metastasis, as was already known regarding the abscopal effect. The combination of local RT with anti-PD-1 blockade could be a promising treatment strategy against metastatic TNBC. Further research is required to integrate our results into a clinical setting.
format Online
Article
Text
id pubmed-8509046
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-85090462021-10-13 Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model Song, Haa-Na Jin, Hana Kim, Jung-Hoon Ha, In-Bong Kang, Ki-Mun Choi, Hoon-Sik Jeong, Ho-Jin Kim, Min-Young Kim, Hye-Jung Jeong, Bae-Kwon Int J Mol Sci Article Local radiotherapy (RT) is important to manage metastatic triple-negative breast cancer (TNBC). Although RT primarily reduces cancer cells locally, this control can be enhanced by triggering the immune system via immunotherapy. RT and immunotherapy may lead to an improved systemic effect, known as the abscopal effect. Here, we analyzed the antitumor effect of combination therapy using RT with an anti-programmed cell death-1 (PD-1) antibody in primary tumors, using poorly immunogenic metastatic mouse mammary carcinoma 4T1 model. Mice were injected subcutaneously into both flanks with 4T1 cells, and treatment was initiated 12 days later. Mice were randomly assigned to three treatment groups: (1) control (no treatment with RT or immune checkpoint inhibitor (ICI)), (2) RT alone, and (3) RT+ICI. The same RT dose was prescribed in both RT-alone and RT+ICI groups as 10Gy/fx in two fractions and delivered to only one of the two tumor burdens injected at both sides of flanks. In the RT+ICI group, 200 µg fixed dose of PD-1 antibody was intraperitoneally administered concurrently with RT. The RT and ICI combination markedly reduced tumor cell growth not only in the irradiated site but also in non-irradiated sites, a typical characteristic of the abscopal effect. This was observed only in radiation-sensitive cancer cells. Lung metastasis development was lower in RT-irradiated groups (RT-only and RT+ICI groups) than in the non-irradiated group, regardless of the radiation sensitivity of tumor cells. However, there was no additive effect of ICI on RT to control lung metastasis, as was already known regarding the abscopal effect. The combination of local RT with anti-PD-1 blockade could be a promising treatment strategy against metastatic TNBC. Further research is required to integrate our results into a clinical setting. MDPI 2021-09-28 /pmc/articles/PMC8509046/ /pubmed/34638817 http://dx.doi.org/10.3390/ijms221910476 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Song, Haa-Na
Jin, Hana
Kim, Jung-Hoon
Ha, In-Bong
Kang, Ki-Mun
Choi, Hoon-Sik
Jeong, Ho-Jin
Kim, Min-Young
Kim, Hye-Jung
Jeong, Bae-Kwon
Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model
title Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model
title_full Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model
title_fullStr Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model
title_full_unstemmed Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model
title_short Abscopal Effect of Radiotherapy Enhanced with Immune Checkpoint Inhibitors of Triple Negative Breast Cancer in 4T1 Mammary Carcinoma Model
title_sort abscopal effect of radiotherapy enhanced with immune checkpoint inhibitors of triple negative breast cancer in 4t1 mammary carcinoma model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509046/
https://www.ncbi.nlm.nih.gov/pubmed/34638817
http://dx.doi.org/10.3390/ijms221910476
work_keys_str_mv AT songhaana abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT jinhana abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT kimjunghoon abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT hainbong abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT kangkimun abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT choihoonsik abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT jeonghojin abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT kimminyoung abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT kimhyejung abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel
AT jeongbaekwon abscopaleffectofradiotherapyenhancedwithimmunecheckpointinhibitorsoftriplenegativebreastcancerin4t1mammarycarcinomamodel