An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice

Abstract

Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86−/− mice produced skin cancer earlier compared with CD80−/− and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80−/−/CD86−/− mice had strongly reduced numbers of UV-induced CD4+CD25+ suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4+CD25+ T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.

8-Methoxypsoralen Plus Ultraviolet A Therapy Acts via Inhibition of the IL-23/Th17 Axis and Induction of Foxp3+ Regulatory T Cells Involving CTLA4 Signaling in a Psoriasis-Like Skin Disorder

“…It remains to be determined how the PUVA-induced regulation of the disturbance of the IL-17/23 axis and the iTregs relate to carcinogenesis upon long-term treatment (54,55). Interestingly, upon chronic UV exposure, Tregs were found to be involved in skin cancer formation in mice (31) and are targeted in human cancer immunotherapy (28). In contrast, IL-23 and IL-17 are increased in human tumors and have been implicated in causing cancer (56).…”

“…Data from earlier studies indicated that treatment of mice with CTLA4Ig, a soluble form of CTLA4 that effectively blocks CD80/CD86 engagement with CD28, suppressed antitumor immunity, transplant rejection, and autoimmune responses (30). Moreover, blocking CTLA4 signaling has been shown to inhibit the suppressive function of UV-induced CD4 + CD25 + T cells (31). We therefore used anti-CTLA4 mAb treatment to test the functional relevance of PUVAinduced Tregs.…”

The Ubiquitin E3 Ligase Cbl-b in T Cells Tolerance and Tumor Immunity

“…For instance, UVB irradiation induces a specific subset of UV regulatory T-cells, which have been shown to suppress effector T-cell responses via IL-10. [109][110][111][112][113] UVB radiation has also been reported to inhibit the Ag-presenting function of dendritic cells, i.e., epidermal Langerhans cells, directly via UVB-induced cytotoxicity as well as indirectly via the release of immunosuppressive cytokines. 114,115 Intriguingly, our recent experiments have demonstrated, that cbl-b -/-mice reject implanted TC-1 tumors as well as spontaneous UVB-induced skin tumors.…”

LED photoprevention: Reduced MED response following multiple LED exposures

“…The most common negative effect is acute sunburn or erythema, but UV insults can also lead to premature photoaging [17][18][19][20][21][22] and carcinogenesis [23][24][25][26][27][28][29]. The identification of novel treatments to increase skin resistance to UV induced damage without the limitations of traditional methods would prove particularly useful.…”