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UVB-induced NF-kB activation is independent of p38, CK2, TAK1 and DDR kinases.

Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates initiation of skin lesions and establishment of tumors by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here, we report that UVR exposure significantly increased expression of immune checkpoint molecule PD-L1 in melanoma cells. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the receptor for advanced glycation endproducts (RAGE) receptor to promote NF-κB– and IRF3-dependent transcription of PD-L1 in melanocytes. UVR exposure significantly reduced the susceptibility of melanoma cells to CD8+ T-cell–dependent cytotoxicity, which was mitigated by inhibiting the HMGB1/TBK1/IRF3/NF-κB cascade or by blocking the PD-1/PD-L1 checkpoint. Taken together, our findings demonstrate that UVR-induced upregulation of PD-L1 contributes to immune suppression in the skin microenvironment, which may promote immune evasion of oncogenic cells and drive melanoma initiation and progression.Significance:These findings identify PD-L1 as a critical component of UV-induced immune suppression in the skin, which facilitates immunoevasion of oncogenic melanocytes and development of melanoma.See related commentary by Sahu, p. 2805

SIRT1 inactivation upon UVR promotes HMGB1 acetylation and secretion.

UVR-promoted melanoma evasion from CTL cytotoxicity, in an IRF3-dependent manner, was mitigated by blocking PD-1/PD-L1.

UVR decreased melanoma susceptibility to CTLs which required IRF3.

RAGE and IRF3 are required for PD-L1 induction by UVB.

PD-L1 is upregulated in skin cells which correlates to NF-kB activation.

Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates initiation of skin lesions and establishment of tumors by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here, we report that UVR exposure significantly increased expression of immune checkpoint molecule PD-L1 in melanoma cells. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the receptor for advanced glycation endproducts (RAGE) receptor to promote NF-κB– and IRF3-dependent transcription of PD-L1 in melanocytes. UVR exposure significantly reduced the susceptibility of melanoma cells to CD8+ T-cell–dependent cytotoxicity, which was mitigated by inhibiting the HMGB1/TBK1/IRF3/NF-κB cascade or by blocking the PD-1/PD-L1 checkpoint. Taken together, our findings demonstrate that UVR-induced upregulation of PD-L1 contributes to immune suppression in the skin microenvironment, which may promote immune evasion of oncogenic cells and drive melanoma initiation and progression. Significance: These findings identify PD-L1 as a critical component of UV-induced immune suppression in the skin, which facilitates immunoevasion of oncogenic melanocytes and development of melanoma. See related commentary by Sahu, p. 2805

The appropriate activation of the adaptive immune system relies upon the reprogramming of naïve T cells into specialized effector T cells that can combat pathogens and tumors. Naïve T cells are actively maintained in a state of hyporesponsiveness termed quiescence, which is characterized by small cell size, low proliferative rate, and low basal metabolism. Engagement of antigen and costimulatory receptors drives T cells to exit quiescence to promote subsequent clonal expansion and functional differentiation. The exit from quiescence, which precedes activation-induced proliferation, is associated with extensive remodeling of cellular morphology and metabolism. Here, we define and discuss the implications of the six key features of the exit of naïve T cells from quiescence: (i) cell-cycle entry, (ii) cell growth, (iii) autocrine or paracrine interleukin-2 signaling, (iv) anabolic metabolism, (v) nutrient uptake, and (vi) remodeling of mitochondrial function. Ultimately, understanding how naïve T cells meet each of these requirements for quiescence exit will allow for the tuning of T-cell responses to treat infectious diseases, autoimmunity, and cancer. Cancer Immunol Res; 6(5); 502–8. ©2018 AACR.

Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates skin lesion initiation and establishment by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here we report that the expression of immune checkpoint molecule PD-L1 was significantly increased in melanocytes and melanoma cells upon UVR exposure. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the RAGE (receptor for advanced glycation endproducts) receptor to promote the NF-κB and IRF3-dependent transcription of PD-L1 in melanocytes. We also found that UVR exposure significantly reduced the susceptibility of melanoma cells to CD8+ T cell-dependent cytotoxicity, which was mitigated by inhibiting the HMGB1/TBK1/IRF3/NF-κB cascade or blocking the PD-1/PD-L1 checkpoint. Taken together, our findings demonstrate that UVR-induced PD-L1 upregulation contributes to the immune suppression in the skin microenvironment, which may promote immune evasion of oncogenic cells, and melanoma initiation and progression. Citation Format: Wei Wang, Nicole Chapman, Bo Zhang, Mingqi Li, Meiyun Fan, R. Nicholas Laribee, M. Raza Zaidi, Lawrence Pfeffer, Hongbo Chi, Zhaohui Wu. HMGB1-activated IRF3 and NF-κB contributes to UV radiation-induced immune suppression by upregulating PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 524.