Celecoxib promotes degranulation of CD8+ T cells in HPV-induced lesions of K14-HPV16 transgenic mice

Abstract

Aims: Human papillomavirus (HPV) is a known biologic carcinogen which is commonly transmitted through sexual intercourse. CD8 + T cells are known effectors against tumour cells and an important prognostic marker in HPV-induced cancers. COX-2 inhibitors enhance CD8 + T cell activity against some cancers. In this work, we sought to study the presence and activation of CD8 + T lymphocytes in lesions from K14-HPV16 transgenic mice and the immunomodulatory effect of celecoxib (CXB) over these cells.Main methods: Skin samples of CXB-treated and untreated HPV16 -/-and HPV16 +/-mice were enzymatically digested and analysed by flow cytometry to assess CD8 + and CD8 + CD107a + T cell infiltrates. Matched skin samples were classified histologically.Key findings: HPV16 +/-mice presented higher CD8 + T cell infiltration than HPV16 -/-animals (P 0.001). Older HPV16 +/-animals showed epidermal dysplasia and increased percentages of CD8 + CD107a + T cells compared with younger animals with hyperplasia (P 0.001), validating this model for testing the effects of celecoxib on CD8 + T cells. CXB-treated HPV16 +/-mice showed higher percentages of CD8 + CD107a + T cells compared with untreated HPV16 +/-animals (P 0.01), but no differences were observed concerning the progression of epidermal lesions.Significance: These findings indicate that celecoxib enhances the degranulation of CD8 + T cells on HPV16-induced lesions, suggesting the potential clinical use of COX-2 inhibitors. Additionally, this study demonstrates the usefulness of the K14-HPV16 mouse model for testing therapeutic immunomodulatory approaches.

Dimethylaminoparthenolide reduces the incidence of dysplasia and ameliorates a wasting syndrome in HPV16‐transgenic mice

“…In fact, HPV oncoproteins are known to upregulate NF‐κB signaling during tumor progression as previously reviewed (Gil da Costa et al, ; Xu et al, ). Multiple anti‐inflammatory compounds have shown chemopreventive activity against HPV‐induced lesions in this model (Gil da Costa et al, ; Santos et al, ).…”

“…Our group and others recently characterized K14-HPV16 transgenic mice as a model to study HPV-driven carcinogenesis (Arbeit et al, 1994;Gil da Costa et al, 2017;Paiva et al, 2015a;Paiva et al, 2015b). Santos et al, 2016).…”

Regulation of miRNA-146a and miRNA-150 Levels by Celecoxib in Premalignant Lesions of K14-HPV16 Mice

“…Our group has already studied the expression of two microRNAs miRNA-21 and miRNA-155 which are related to the inflammatory process in this model (14)(15). More recently, we showed that a relatively high dose (124 mg/kg/day) of celecoxib, a selective COX-2 inhibitor, promotes degranulation of CD8+ T cells in this model (17), while ptaquiloside, a natural immunosuppresive agent from Pteridium spp., down-regulates it (23).…”

“…K14-HPV16 transgenic mice target all HPV16 oncogenes to keratinized epithelia, reproducing essential molecular and morphological aspects of HPV16 induced premalignant lesions and various types of cancer (16). Using the same model, we also reported that the anti-inflammatory drug celecoxib, a selective cycloxigenase-2 (COX-2) inhibitor, is able to up-regulate degranulation of CD8 + T cells in HPV16 induced lesions (17). In the same experiment, celecoxib was also able to reduce the inflammation associated with HPV induced lesions and lesions' progression.…”

The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations

“…Cyclooxygenase-2 (COX-2), a key mediator of inflammation, is involved in the development of multiple types of cancer, such as colon cancer, making it a useful therapeutic target [10,11,12,13]. We have previously shown that a specific COX-2 inhibitor, celecoxib, was able to block the progression of HPV16-induced lesions in transgenic mice [14]. However, oral administration of celecoxib induced significant mortality in HPV16 transgenic mice, indicating that it has unacceptable toxicity in our animal model.…”