Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control

Abstract

The frequent occurrence of cutaneous squamous cell carcinomas (SCCs) containing weakly tumorigenic human papillomaviruses (HPVs) following iatrogenic immunosuppression for organ transplantation remains incompletely understood. Here we address this problem in the light of recent insights into (1) the association of low-risk β-HPVs with skin SCCs in the rare genetic syndromes of epidermodysplasia verruciformis and xeroderma pigmentosum, (2) the frequent recovery of post-transplant tumor control on substituting calcineurin-inhibitory with mTOR-inhibitory immunosuppression, (3) the unexpectedly favorable prognosis of node-positive SCCs containing high-risk α-HPVs originating in the activated immune niche of the oropharynx, (4) the rapid occurrence of HPV-negative SCCs in ultraviolet (UV)-damaged skin of melanoma patients receiving Raf-inhibitory drugs, and (5) the selective ability of β-HPV E6 oncoproteins to inhibit Notch tumor-suppressive signaling in cutaneous and mesenchymal tissues. The crosstalk so implied between oncogenic UV-induced mutations, defective host immunity, and β-HPV-dependent stromal-epithelial signaling suggests that immunosuppressants such as calcineurin inhibitors intensify mitogenic signalling in TP53-mutant keratinocytes while also abrogating immune-dependent Notch-mediated tumor repression. This emerging interplay between solar damage, viral homeostasis and immune control makes it timely to reappraise strategies for managing skin SCCs in transplant patients.

Keywords: AIDS; BCC; CNI; Carcinogenesis; EGFR; EMT; EV; HIV; HPV; IFN; Immunosuppression; Papillomavirus; SCC; SCID; Skin cancer; UV; Vaccines; XP; acquired immunodeficiency syndrome; basal cell carcinoma; calcineurin inhibitor; epidermal growth factor receptor; epidermodysplasia verruciformis; epithelial–mesenchymal transition; human immunodeficiency virus; human papillomavirus; interferon; mTOR; mammalian target of rapamycin; severe combined immunodeficiency; squamous cell carcinoma; ultraviolet light; xeroderma pigmentosum.