TY - JOUR

T1 - Anti-pd-1 therapy with adjuvant ablative fractional laser improves anti-tumor response in basal cell carcinomas

AU - Olesen, Uffe Høgh

AU - Wiinberg, Martin

AU - Lerche, Catharina Margrethe

AU - Jæhger, Ditte Elisabeth

AU - Andresen, Thomas Lars

AU - Haedersdal, Merete

N1 - Funding Information: Funding: The research was supported (M. Haedersdal) by the Leo Foundation (LF18045) and was executed as part of the Skin Cancer Innovation Clinical Academic Group (SCIN-CAG) of Greater Copenhagen Health Science Partners (GCHSP) and the Danish Skin Cancer Research Center. Funding Information: Acknowledgments: The authors would like to thank Diana Høeg, Catrine F. Goldschmidt, and Martin Glud (Department of Dermatology, Copenhagen University Hospital Bispebjerg and Frederiks-berg) for the technical assistance and histological evaluations during this study. The Ptch1+/− K14-CreER2 p53fl/fl mouse strain was kindly provided by Ervin H. Epstein (Children’s Hospital Oakland Research Institute, Oakland, CA, USA). The research was supported by the Leo Foundation (LF18045) and was executed as part of Skin Cancer Innovation clinical academic group (SCIN-CAG) of Greater Copenhagen Health Science Partners (GCHSP) and the Danish Skin Cancer Research Center. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021

Y1 - 2021

N2 - The efficacy of anti-programmedcelldeath1therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC) treatment, can be enhanced by adjuvant ablative fractional laser (AFL) in syngeneic murine tumor models. In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant autochthonous BCC model. BCC tumors (n = 72) were induced in Ptch1+/−K14-CreER2p53fl/fl-mice (n = 34), and the mice subsequently received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. The outcome measures included mouse survival time, tumor clearance, tumor growth rates, and tumor immune infiltration. Both aPD-1 and AFL alone significantly increased survival time relative to untreated controls (31 d and 34.5 d, respectively vs. 14 d, p = 0.0348–0.0392). Complementing aPD-1 with AFL further promoted survival (60 d, p = 0.0198 vs. aPD-1) and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in the tumors. Similar to AFL alone, combined aPD-1 and AFL increased neutrophil counts (4-fold, p = 0.0242), the proportion of MHCII-positive neutrophils (p = 0.0121), and concordantly, CD4+ and CD8+ T-cell infiltration (p = 0.0061–0.0242). These descriptive results suggest that the anti-tumor response that is generated by aPD-1 with adjuvant AFL is potentially promoted by increased neutrophil and T-cell engraftment in tumors. In conclusion, local AFL shows substantial promise as an adjuvant to systemic aPD-1 therapy in a clinically relevant preclinical BCC model.

AB - The efficacy of anti-programmedcelldeath1therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC) treatment, can be enhanced by adjuvant ablative fractional laser (AFL) in syngeneic murine tumor models. In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant autochthonous BCC model. BCC tumors (n = 72) were induced in Ptch1+/−K14-CreER2p53fl/fl-mice (n = 34), and the mice subsequently received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. The outcome measures included mouse survival time, tumor clearance, tumor growth rates, and tumor immune infiltration. Both aPD-1 and AFL alone significantly increased survival time relative to untreated controls (31 d and 34.5 d, respectively vs. 14 d, p = 0.0348–0.0392). Complementing aPD-1 with AFL further promoted survival (60 d, p = 0.0198 vs. aPD-1) and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in the tumors. Similar to AFL alone, combined aPD-1 and AFL increased neutrophil counts (4-fold, p = 0.0242), the proportion of MHCII-positive neutrophils (p = 0.0121), and concordantly, CD4+ and CD8+ T-cell infiltration (p = 0.0061–0.0242). These descriptive results suggest that the anti-tumor response that is generated by aPD-1 with adjuvant AFL is potentially promoted by increased neutrophil and T-cell engraftment in tumors. In conclusion, local AFL shows substantial promise as an adjuvant to systemic aPD-1 therapy in a clinically relevant preclinical BCC model.

KW - Ablative fractional laser

KW - Autochthonous cancer model

KW - Basal cell carcinoma

KW - Immunotherapy

KW - Programmed cell death-1 inhibitor

U2 - 10.3390/cancers13246326

DO - 10.3390/cancers13246326

M3 - Journal article

C2 - 34944945

AN - SCOPUS:85121141601

VL - 13

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 24

M1 - 6326

ER -