Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models
Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotyp...
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| Format: | Article |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1166180/full |
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| author | Emile J. Clappaert Emile J. Clappaert Emile J. Clappaert Daliya Kancheva Daliya Kancheva Daliya Kancheva Jan Brughmans Jan Brughmans Ayla Debraekeleer Ayla Debraekeleer Pauline M. R. Bardet Pauline M. R. Bardet Yvon Elkrim Yvon Elkrim Dagmar Lacroix Dagmar Lacroix Maida Živalj Maida Živalj Ahmed E.I. Hamouda Ahmed E.I. Hamouda Jo A. Van Ginderachter Jo A. Van Ginderachter Sofie Deschoemaeker Sofie Deschoemaeker Damya Laoui Damya Laoui |
| author_facet | Emile J. Clappaert Emile J. Clappaert Emile J. Clappaert Daliya Kancheva Daliya Kancheva Daliya Kancheva Jan Brughmans Jan Brughmans Ayla Debraekeleer Ayla Debraekeleer Pauline M. R. Bardet Pauline M. R. Bardet Yvon Elkrim Yvon Elkrim Dagmar Lacroix Dagmar Lacroix Maida Živalj Maida Živalj Ahmed E.I. Hamouda Ahmed E.I. Hamouda Jo A. Van Ginderachter Jo A. Van Ginderachter Sofie Deschoemaeker Sofie Deschoemaeker Damya Laoui Damya Laoui |
| author_sort | Emile J. Clappaert |
| collection | DOAJ |
| description | Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy. |
| first_indexed | 2024-03-12T16:13:43Z |
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| id | doaj.art-ad19eef033c8482bbb80dc7e46ef2740 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T16:13:43Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-ad19eef033c8482bbb80dc7e46ef27402023-08-09T11:09:44ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.11661801166180Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer modelsEmile J. Clappaert0Emile J. Clappaert1Emile J. Clappaert2Daliya Kancheva3Daliya Kancheva4Daliya Kancheva5Jan Brughmans6Jan Brughmans7Ayla Debraekeleer8Ayla Debraekeleer9Pauline M. R. Bardet10Pauline M. R. Bardet11Yvon Elkrim12Yvon Elkrim13Dagmar Lacroix14Dagmar Lacroix15Maida Živalj16Maida Živalj17Ahmed E.I. Hamouda18Ahmed E.I. Hamouda19Jo A. Van Ginderachter20Jo A. Van Ginderachter21Sofie Deschoemaeker22Sofie Deschoemaeker23Damya Laoui24Damya Laoui25Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumConventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1166180/fulldendritic cellimmunotherapybreast cancerFlt3Lcombination therapieslung cancer |
| spellingShingle | Emile J. Clappaert Emile J. Clappaert Emile J. Clappaert Daliya Kancheva Daliya Kancheva Daliya Kancheva Jan Brughmans Jan Brughmans Ayla Debraekeleer Ayla Debraekeleer Pauline M. R. Bardet Pauline M. R. Bardet Yvon Elkrim Yvon Elkrim Dagmar Lacroix Dagmar Lacroix Maida Živalj Maida Živalj Ahmed E.I. Hamouda Ahmed E.I. Hamouda Jo A. Van Ginderachter Jo A. Van Ginderachter Sofie Deschoemaeker Sofie Deschoemaeker Damya Laoui Damya Laoui Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models Frontiers in Immunology dendritic cell immunotherapy breast cancer Flt3L combination therapies lung cancer |
| title | Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models |
| title_full | Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models |
| title_fullStr | Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models |
| title_full_unstemmed | Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models |
| title_short | Flt3L therapy increases the abundance of Treg-promoting CCR7+ cDCs in preclinical cancer models |
| title_sort | flt3l therapy increases the abundance of treg promoting ccr7 cdcs in preclinical cancer models |
| topic | dendritic cell immunotherapy breast cancer Flt3L combination therapies lung cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1166180/full |
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