| First Author | Lewis JM | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 37 | PubMed ID | 34504008 |
| Mgi Jnum | J:310224 | Mgi Id | MGI:6762138 |
| Doi | 10.1073/pnas.2016963118 | Citation | Lewis JM, et al. (2021) Chronic UV radiation-induced RORgammat+ IL-22-producing lymphoid cells are associated with mutant KC clonal expansion. Proc Natl Acad Sci U S A 118(37):e2016963118 |
| abstractText | Chronic ultraviolet (UV) radiation exposure is the greatest risk factor for cutaneous squamous cell carcinoma (cSCC) development, and compromised immunity accelerates this risk. Having previously identified that epidermal Langerhans cells (LC) facilitate the expansion of UV-induced mutant keratinocytes (KC), we sought to more fully elucidate the immune pathways critical to cutaneous carcinogenesis and to identify potential targets of intervention. Herein, we reveal that chronic UV induces and LC enhance a local immune shift toward RORgammat+ interleukin (IL)-22/IL-17A-producing cells that occurs in the presence or absence of T cells while identifying a distinct RORgammat+ Sca-1+ CD103+ ICOS+ CD2(+/-) CCR6+ intracellular CD3+ cutaneous innate lymphoid cell type-3 (ILC3) population (uvILC3) that is associated with UV-induced mutant KC growth. We further show that mutant KC clone size is markedly reduced in the absence of RORgammat+ lymphocytes or IL-22, both observed in association with expanding KC clones, and find that topical application of a RORgamma/gammat inhibitor during chronic UV exposure reduces local expression of IL-22 and IL-17A while markedly limiting mutant p53 KC clonal expansion. We implicate upstream Toll-like receptor signaling in driving this immune response to chronic UV exposure, as MyD88/Trif double-deficient mice also show substantially reduced p53 island number and size. These data elucidate key immune components of chronic UV-induced cutaneous carcinogenesis that might represent targets for skin cancer prevention. |
