Abstract PO063: Transcriptomic analysis identifies changes in gene expression in Actinic Keratoses after treatment with imiquimod and differential gene expression
Authors: Trager Megan H. , Rizk Emanuelle , Rose Sharon , Lau Branden , Fullerton Ben , Zhu Kuixi , Pradhan Jaya , Moore Michael , Chandra Ayush , Bogardus Margaret , Singer Giselle , Gartrell-Corrado Robyn , Chang Rui , Geskin Larisa , Saenger Yvonne , Goldenbery Gary 
Published: February 2021

Background: The presence of actinic keratoses (AKs) increases a patient’s risk of developing squamous cell carcinoma (SCC) by greater than six-fold. It is difficult to predict which AKs will progress to become SCC, and topical treatments such as imiquimod are used to treat the entire affected field indiscriminately, effectively eliminating AKs in 50% of patients but sometimes resulting in severe inflammation and pain. Defining biomarkers to predict response to treatment would be helpful to guide therapy. Objectives: To evaluate the effect of imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment in patients treated with imiquimod.

Methods: Biopsies were collected prospectively from 21 patients with presumptive AK and examined histologically. All patients were treated with imiquimod 3.75% on a short cyclical treatment regimen. 19 patients had available pre-treatment AK biopsies and 14 patients had paired pre- and post-treatment biopsies. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay.

Results: Imiquimod significantly decreased total number of AKs by study endpoint at week 14 (p&lt;0.0001). Post-imiquimod therapy, levels of CDK1, CXCL13, IL1B, GADPH, TTK, ILF3, EWSR1, BIRC5, PLAUR, ISG20, and C1QBP were significantly lower (p&lt;0.05 after adjustment for multiple comparisons), with CXCL13 and IL1B showing a greater than 2-log2 fold decrease in expression post-treatment. Complete responders (CR) exhibited a distinct pattern of inflammatory gene expression pre-treatment relative to incomplete responders (IR), with significant alterations in 15 inflammatory pathways (p&lt;0.05) reflecting differential expression of 103 genes, of which 95 were upregulated in CR (p&lt;0.05). Presence of adverse effects was found to be related to an improved treatment response.

Conclusions: NanoString analysis of AKs pre- and post-treatment with imiquimod shows downregulation of genes implicated in oncogenesis and immune suppression. Differences in gene expression were found between pre-treatment samples in CR versus IR, suggesting that higher levels of inflammation pre-treatment may play a part in regression of AKs. Further, presence of adverse effects in response to therapy was associated with an improved response to imiquimod. These findings show that the pre-treatment immune micro-environment impacts responsiveness of AKs to imiquimod and that clinical inflammation during treatment is associated with AK resolution. Further characterization of the immune micro-environment in AKs may help develop biomarkers predictive of response to topical immune modulators and may guide therapy in patients with high numbers of AKs at risk for SCC.

Citation Format: Megan H. Trager, Emanuelle Rizk, Sharon Rose, Branden Lau, Ben Fullerton, Kuixi Zhu, Jaya Pradhan, Michael Moore, Ayush Chandra, Margaret Bogardus, Giselle Singer, Robyn Gartrell-Corrado, Rui Chang, Larisa Geskin, Yvonne Saenger, Gary Goldenbery. Transcriptomic analysis identifies changes in gene expression in Actinic Keratoses after treatment with imiquimod and differential gene expression [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO063.