Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment

Research output: Contribution to journalJournal articlepeer-review

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Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment. / Fontenete, Silvia; Lerche, Catharina M.; Paasch, Uwe; Perez-Moreno, Mirna; Olesen, Uffe H.; Haedersdal, Merete.

In: Lasers in Surgery and Medicine, Vol. 53, No. 9, 2021, p. 1227-1237.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Fontenete, S, Lerche, CM, Paasch, U, Perez-Moreno, M, Olesen, UH & Haedersdal, M 2021, 'Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment', Lasers in Surgery and Medicine, vol. 53, no. 9, pp. 1227-1237. https://doi.org/10.1002/lsm.23406

APA

Fontenete, S., Lerche, C. M., Paasch, U., Perez-Moreno, M., Olesen, U. H., & Haedersdal, M. (2021). Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment. Lasers in Surgery and Medicine, 53(9), 1227-1237. https://doi.org/10.1002/lsm.23406

Vancouver

Fontenete S, Lerche CM, Paasch U, Perez-Moreno M, Olesen UH, Haedersdal M. Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment. Lasers in Surgery and Medicine. 2021;53(9):1227-1237. https://doi.org/10.1002/lsm.23406

Author

Fontenete, Silvia ; Lerche, Catharina M. ; Paasch, Uwe ; Perez-Moreno, Mirna ; Olesen, Uffe H. ; Haedersdal, Merete. / Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment. In: Lasers in Surgery and Medicine. 2021 ; Vol. 53, No. 9. pp. 1227-1237.

Bibtex

@article{faf46766ff8e4da4ac2e2ccaf7f741d1,
title = "Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment",
abstract = "Background and Objectives Keratinocyte carcinoma (KC) is the most common cancer worldwide, and squamous cell carcinoma (SCC) is the second most frequent subtype. Ablative fractional laser (AFL)-assisted drug delivery significantly enhances the uptake of topically applied drugs. The objective of this study was to assess tumor response and perform a descriptive characterization of the local recruitment of immune cells and systemic immune mediator levels in an ultraviolet radiation (UVR)-induced murine SCC model after AFL treatment alone and combined with topical imiquimod.Study Design/Materials and Methods Immunocompetent hairless mice (C3 center dot Cg/TifBomTac, n = 74) were irradiated with solar-simulated UVR until 3-mm SCCs developed. The mice were divided into four interventional groups: AFL alone, AFL + imiquimod, imiquimod alone, and untreated SCC controls. AFL was given as a single treatment, whereas imiquimod was applied daily until the mice were euthanized on Days 0, 2, 7, or 14. SCCs were photographed and measured (mm) to assess the therapeutic response. Skin samples were processed for histopathological and immunohistochemical analyses, as well as for flow cytometry. Cytokine expression changes in sera were analyzed using ELISpot cytokine arrays.Results Treatment of mouse SCCs with AFL + imiquimod induced the most robust immune cell infiltration and the greatest proportion of tumor clearance compared to other interventions. Early innate immune cell infiltration was induced by AFL + imiquimod treatment as the number of neutrophils and macrophages had increased fourfold within 2 days of treatment initiation compared with untreated SCC control mice (P <0.05). AFL treatment alone had a more limited effect, with a fourfold increase in neutrophils (P <0.05) but no significant increase in the number of macrophages. Correspondingly, treatment with AFL + imiquimod had the greatest effects on the adaptive immune cell recruitment: CD4(+) T-helper cells increased threefold at Day 7 compared with untreated SCCs (P = 0.0001) and, notably, cytotoxic CD8(+) T cells increased 14-fold at Day 14 (P = 0.0112). In addition, FOXP3(+) regulatory T cells (Tregs) increased 14-fold at Day 7 (P = 0.0026), suggesting the resolution of the inflammatory infiltration. AFL treatment alone induced a moderate immune cell infiltration (a twofold increase in CD4(+) T-helper cells, P = 0.0200; a threefold increase in CD8(+) T cells, P = 0.0100; and a 14-fold increase in FOXP3(+) Tregs at Day 14, P = 0.0021), whereas imiquimod alone did not significantly increase cell counts. AFL + imiquimod treatment increased CXCL12 serum levels threefold at Day 14 (P = 0.0200).Conclusion AFL treatment alone and in combination with imiquimod induces substantial tumor clearance associated with local recruitment of innate and adaptive immune cells in UVR-induced murine SCCs. These results may provide a basis for new immunotherapeutic approaches to KC treatment.",
keywords = "ablative fractional laser, imiquimod, immune cell recruitment, keratinocyte carcinoma, squamous cell carcinoma",
author = "Silvia Fontenete and Lerche, {Catharina M.} and Uwe Paasch and Mirna Perez-Moreno and Olesen, {Uffe H.} and Merete Haedersdal",
year = "2021",
doi = "10.1002/lsm.23406",
language = "English",
volume = "53",
pages = "1227--1237",
journal = "Lasers in Surgery and Medicine",
issn = "0196-8092",
publisher = "JohnWiley & Sons, Inc.",
number = "9",

}

RIS

TY - JOUR

T1 - Tumor Clearance and Immune Cell Recruitment in UV-Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment

AU - Fontenete, Silvia

AU - Lerche, Catharina M.

AU - Paasch, Uwe

AU - Perez-Moreno, Mirna

AU - Olesen, Uffe H.

AU - Haedersdal, Merete

PY - 2021

Y1 - 2021

N2 - Background and Objectives Keratinocyte carcinoma (KC) is the most common cancer worldwide, and squamous cell carcinoma (SCC) is the second most frequent subtype. Ablative fractional laser (AFL)-assisted drug delivery significantly enhances the uptake of topically applied drugs. The objective of this study was to assess tumor response and perform a descriptive characterization of the local recruitment of immune cells and systemic immune mediator levels in an ultraviolet radiation (UVR)-induced murine SCC model after AFL treatment alone and combined with topical imiquimod.Study Design/Materials and Methods Immunocompetent hairless mice (C3 center dot Cg/TifBomTac, n = 74) were irradiated with solar-simulated UVR until 3-mm SCCs developed. The mice were divided into four interventional groups: AFL alone, AFL + imiquimod, imiquimod alone, and untreated SCC controls. AFL was given as a single treatment, whereas imiquimod was applied daily until the mice were euthanized on Days 0, 2, 7, or 14. SCCs were photographed and measured (mm) to assess the therapeutic response. Skin samples were processed for histopathological and immunohistochemical analyses, as well as for flow cytometry. Cytokine expression changes in sera were analyzed using ELISpot cytokine arrays.Results Treatment of mouse SCCs with AFL + imiquimod induced the most robust immune cell infiltration and the greatest proportion of tumor clearance compared to other interventions. Early innate immune cell infiltration was induced by AFL + imiquimod treatment as the number of neutrophils and macrophages had increased fourfold within 2 days of treatment initiation compared with untreated SCC control mice (P <0.05). AFL treatment alone had a more limited effect, with a fourfold increase in neutrophils (P <0.05) but no significant increase in the number of macrophages. Correspondingly, treatment with AFL + imiquimod had the greatest effects on the adaptive immune cell recruitment: CD4(+) T-helper cells increased threefold at Day 7 compared with untreated SCCs (P = 0.0001) and, notably, cytotoxic CD8(+) T cells increased 14-fold at Day 14 (P = 0.0112). In addition, FOXP3(+) regulatory T cells (Tregs) increased 14-fold at Day 7 (P = 0.0026), suggesting the resolution of the inflammatory infiltration. AFL treatment alone induced a moderate immune cell infiltration (a twofold increase in CD4(+) T-helper cells, P = 0.0200; a threefold increase in CD8(+) T cells, P = 0.0100; and a 14-fold increase in FOXP3(+) Tregs at Day 14, P = 0.0021), whereas imiquimod alone did not significantly increase cell counts. AFL + imiquimod treatment increased CXCL12 serum levels threefold at Day 14 (P = 0.0200).Conclusion AFL treatment alone and in combination with imiquimod induces substantial tumor clearance associated with local recruitment of innate and adaptive immune cells in UVR-induced murine SCCs. These results may provide a basis for new immunotherapeutic approaches to KC treatment.

AB - Background and Objectives Keratinocyte carcinoma (KC) is the most common cancer worldwide, and squamous cell carcinoma (SCC) is the second most frequent subtype. Ablative fractional laser (AFL)-assisted drug delivery significantly enhances the uptake of topically applied drugs. The objective of this study was to assess tumor response and perform a descriptive characterization of the local recruitment of immune cells and systemic immune mediator levels in an ultraviolet radiation (UVR)-induced murine SCC model after AFL treatment alone and combined with topical imiquimod.Study Design/Materials and Methods Immunocompetent hairless mice (C3 center dot Cg/TifBomTac, n = 74) were irradiated with solar-simulated UVR until 3-mm SCCs developed. The mice were divided into four interventional groups: AFL alone, AFL + imiquimod, imiquimod alone, and untreated SCC controls. AFL was given as a single treatment, whereas imiquimod was applied daily until the mice were euthanized on Days 0, 2, 7, or 14. SCCs were photographed and measured (mm) to assess the therapeutic response. Skin samples were processed for histopathological and immunohistochemical analyses, as well as for flow cytometry. Cytokine expression changes in sera were analyzed using ELISpot cytokine arrays.Results Treatment of mouse SCCs with AFL + imiquimod induced the most robust immune cell infiltration and the greatest proportion of tumor clearance compared to other interventions. Early innate immune cell infiltration was induced by AFL + imiquimod treatment as the number of neutrophils and macrophages had increased fourfold within 2 days of treatment initiation compared with untreated SCC control mice (P <0.05). AFL treatment alone had a more limited effect, with a fourfold increase in neutrophils (P <0.05) but no significant increase in the number of macrophages. Correspondingly, treatment with AFL + imiquimod had the greatest effects on the adaptive immune cell recruitment: CD4(+) T-helper cells increased threefold at Day 7 compared with untreated SCCs (P = 0.0001) and, notably, cytotoxic CD8(+) T cells increased 14-fold at Day 14 (P = 0.0112). In addition, FOXP3(+) regulatory T cells (Tregs) increased 14-fold at Day 7 (P = 0.0026), suggesting the resolution of the inflammatory infiltration. AFL treatment alone induced a moderate immune cell infiltration (a twofold increase in CD4(+) T-helper cells, P = 0.0200; a threefold increase in CD8(+) T cells, P = 0.0100; and a 14-fold increase in FOXP3(+) Tregs at Day 14, P = 0.0021), whereas imiquimod alone did not significantly increase cell counts. AFL + imiquimod treatment increased CXCL12 serum levels threefold at Day 14 (P = 0.0200).Conclusion AFL treatment alone and in combination with imiquimod induces substantial tumor clearance associated with local recruitment of innate and adaptive immune cells in UVR-induced murine SCCs. These results may provide a basis for new immunotherapeutic approaches to KC treatment.

KW - ablative fractional laser

KW - imiquimod

KW - immune cell recruitment

KW - keratinocyte carcinoma

KW - squamous cell carcinoma

U2 - 10.1002/lsm.23406

DO - 10.1002/lsm.23406

M3 - Journal article

C2 - 33811359

VL - 53

SP - 1227

EP - 1237

JO - Lasers in Surgery and Medicine

JF - Lasers in Surgery and Medicine

SN - 0196-8092

IS - 9

ER -

ID: 259991253