Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated Fibroblasts Article Swipe
Daisuke Shimizu
,
Ryo Yuge
,
Yuki Kitadai
,
Misa Ariyoshi
,
Ryo Miyamoto
,
Yuichi Hiyama
,
Hidehiko Takigawa
,
Yuji Urabe
,
Shiro Oka
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.3390/ijms25137001
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.3390/ijms25137001
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.
Related Topics
Concepts
Tumor microenvironment
Colorectal cancer
Cancer-Associated Fibroblasts
Cancer research
Immune system
Cancer
Cancer immunotherapy
Tumor-associated macrophage
Immunotherapy
Immune checkpoint
Immunity
CD8
Medicine
Macrophage
Immunology
In vitro
Biology
Internal medicine
Biochemistry
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3390/ijms25137001
- https://www.mdpi.com/1422-0067/25/13/7001/pdf?version=1720434781
- OA Status
- gold
- Cited By
- 11
- References
- 52
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4400091912
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4400091912Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3390/ijms25137001Digital Object Identifier
- Title
-
Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated FibroblastsWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-06-26Full publication date if available
- Authors
-
Daisuke Shimizu, Ryo Yuge, Yuki Kitadai, Misa Ariyoshi, Ryo Miyamoto, Yuichi Hiyama, Hidehiko Takigawa, Yuji Urabe, Shiro OkaList of authors in order
- Landing page
-
https://doi.org/10.3390/ijms25137001Publisher landing page
- PDF URL
-
https://www.mdpi.com/1422-0067/25/13/7001/pdf?version=1720434781Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.mdpi.com/1422-0067/25/13/7001/pdf?version=1720434781Direct OA link when available
- Concepts
-
Tumor microenvironment, Colorectal cancer, Cancer-Associated Fibroblasts, Cancer research, Immune system, Cancer, Cancer immunotherapy, Tumor-associated macrophage, Immunotherapy, Immune checkpoint, Immunity, CD8, Medicine, Macrophage, Immunology, In vitro, Biology, Internal medicine, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
11Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 7, 2024: 4Per-year citation counts (last 5 years)
- References (count)
-
52Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.(CRC) | 24 |
| abstract_inverted_index.Here, | 27 |
| abstract_inverted_index.While | 116 |
| abstract_inverted_index.cells | 111 |
| abstract_inverted_index.human | 66 |
| abstract_inverted_index.known | 8 |
| abstract_inverted_index.minor | 121 |
| abstract_inverted_index.model | 89 |
| abstract_inverted_index.mouse | 72, 88 |
| abstract_inverted_index.nest. | 115 |
| abstract_inverted_index.novel | 175 |
| abstract_inverted_index.roles | 12 |
| abstract_inverted_index.their | 19, 57 |
| abstract_inverted_index.tumor | 14, 40, 114, 124, 133, 142, 161 |
| abstract_inverted_index.vitro | 44 |
| abstract_inverted_index.vivo. | 47 |
| abstract_inverted_index.(CAFs) | 6 |
| abstract_inverted_index.(TAMs) | 2 |
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| abstract_inverted_index.immune | 162 |
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| abstract_inverted_index.remain | 25 |
| abstract_inverted_index.showed | 139 |
| abstract_inverted_index.tumors | 73 |
| abstract_inverted_index.PLX3397 | 127, 171 |
| abstract_inverted_index.RNA-seq | 135 |
| abstract_inverted_index.between | 77 |
| abstract_inverted_index.effects | 31 |
| abstract_inverted_index.growth, | 125 |
| abstract_inverted_index.growth. | 134 |
| abstract_inverted_index.induced | 56 |
| abstract_inverted_index.numbers | 78, 82 |
| abstract_inverted_index.reduced | 132 |
| abstract_inverted_index.therapy | 138 |
| abstract_inverted_index.antibody | 130 |
| abstract_inverted_index.depleted | 104 |
| abstract_inverted_index.factor-1 | 101 |
| abstract_inverted_index.involved | 148 |
| abstract_inverted_index.receptor | 102 |
| abstract_inverted_index.resected | 65 |
| abstract_inverted_index.revealed | 74 |
| abstract_inverted_index.summary, | 145 |
| abstract_inverted_index.unclear. | 26 |
| abstract_inverted_index.(PLX3397) | 103 |
| abstract_inverted_index.anti-PD-1 | 129 |
| abstract_inverted_index.attracted | 53 |
| abstract_inverted_index.combining | 126 |
| abstract_inverted_index.following | 136 |
| abstract_inverted_index.immunity, | 41 |
| abstract_inverted_index.immunity. | 143 |
| abstract_inverted_index.increased | 108 |
| abstract_inverted_index.induction | 151 |
| abstract_inverted_index.inhibitor | 97 |
| abstract_inverted_index.monocytes | 54 |
| abstract_inverted_index.represent | 173 |
| abstract_inverted_index.specimens | 68 |
| abstract_inverted_index.treatment | 94, 118 |
| abstract_inverted_index.activation | 140 |
| abstract_inverted_index.colorectal | 22 |
| abstract_inverted_index.macrophage | 156 |
| abstract_inverted_index.migration, | 38 |
| abstract_inverted_index.monocytes, | 51 |
| abstract_inverted_index.orthotopic | 92 |
| abstract_inverted_index.supportive | 11 |
| abstract_inverted_index.surgically | 64 |
| abstract_inverted_index.co-cultured | 49 |
| abstract_inverted_index.combination | 137, 166 |
| abstract_inverted_index.correlation | 76 |
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| abstract_inverted_index.macrophages | 1, 106 |
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| abstract_inverted_index.CD8-positive | 109 |
| abstract_inverted_index.infiltrating | 112 |
| abstract_inverted_index.interactions | 20 |
| abstract_inverted_index.investigated | 29 |
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| abstract_inverted_index.mobilization | 153 |
| abstract_inverted_index.progression, | 17 |
| abstract_inverted_index.transplanted | 71 |
| abstract_inverted_index.immunotherapy | 169 |
| abstract_inverted_index.significantly | 131 |
| abstract_inverted_index.orthotopically | 70 |
| abstract_inverted_index.Immunohistology | 62 |
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| abstract_inverted_index.Tumor-associated | 0 |
| abstract_inverted_index.differentiation, | 37 |
| abstract_inverted_index.transplantation, | 93 |
| abstract_inverted_index.cancer-associated | 4 |
| abstract_inverted_index.microenvironment, | 163 |
| abstract_inverted_index.colony-stimulating | 100 |
| abstract_inverted_index.colon-cancer-derived | 33 |
| cited_by_percentile_year.max | 99 |
| cited_by_percentile_year.min | 97 |
| corresponding_author_ids | https://openalex.org/A5014792788 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 9 |
| corresponding_institution_ids | https://openalex.org/I4210125056 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.7099999785423279 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.93333069 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |