Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity.

Inhibition of T cell infiltration dampens antitumor immunity and causes resistance to immune checkpoint blockade (ICB) therapy. By in vivo CRISPR screening in B16F10 melanoma in female mice, here we report that loss of melanocortin-1 receptor (MC1R) in melanoma cells activates antitumor T cell response and overcomes resistance to ICB. Depletion of MC1R from another melanocytic melanoma model HCmel1274 also enhances ICB efficacy. By activating the GNAS-PKA axis, MC1R inhibits interferon-gamma induced CXCL9/10/11 transcription, thus impairing T cell infiltration into the tumor microenvironment. In human melanomas, high MC1R expression correlates with reduced CXCL9/10/11 expression, impaired T cell infiltration, and poor patient prognosis. Whereas MC1R activation is restricted to melanoma, GNAS activation by hotspot mutations is observed across diverse cancer types and is associated with reduced CXCL9/10/11 expression. Our study implicates MC1R as a melanoma immunotherapy target and suggests GNAS-PKA signaling as a pan-cancer oncogenic pathway inhibiting antitumor T cell response.

Impact of human capital and financial globalization on environmental degradation in OBOR countries: Critical role of national cultural orientations.

As regional economic integration and climate change are among the most important phenomena influencing economic and social sustainability in the modern world, a huge volume of research is directed towards these topics nowadays. The aim of this study is to explore the impact of financial globalization and human capital on environmental degradation in One Belt One Road (OBOR) countries in a cultural context that is largely under-explored in spite of being immensely crucial for fulfilling the United Nations' agenda on climate change mitigation. Owing to the presence of vast cultural differences, we check if the national scores on "Power Distance Index" and "Uncertainty Avoidance" in these countries matter for the environment. To this end, we use the latest and annual data set comprising 31 OBOR countries from 1996 to 2018, and employ panel econometric techniques that effectively deal with the threat of endogeneity. Results show that human capital improves environment while financial globalization deteriorates it. Interestingly, high power distance and uncertainty avoidance can reverse the positive impact of human capital. Similarly, financial globalization is favorable for environment in countries with low power distance and uncertainty avoidance. The findings are robust to the use of alternative specifications. Theoretical underpinnings and implications are discussed arising from the interesting reversal of traditional impacts in different cultural scenarios. Specifically, we recommend a culture of entrepreneurship, innovation, and inclusivity, promoted through increased tolerance towards risk-taking and participative decision-making to reap the benefits of human capital and globalization in improving the environment. Our results have important implications for climate change mitigation endeavors in OBOR countries and understanding the cultural context in this regard. Additionally, our study opens a vast avenue for the related research work in the future.

SIKE of black carp is a substrate of TBK1 and suppresses TBK1-mediated antiviral signaling.

RIG-I like receptor (RLR) signaling functions importantly in host innate immune response against RNA virus, which is tightly regulated by a number of mechanisms to prevent aberrant interferon production. The suppressor of IKKε (SIKE) has been identified as a suppressor of IKKε and TBK1, which are key components of RLR signaling. In this study, SIKE homologue (bcSIKE) of black carp (Mylopharyngodon piceus) has been cloned and characterized. The transcription of bcSIKE varied in host cells in response to the stimulation of LPS, poly (I:C) and viruses. bcSIKE migrated around 27 KDa in immunoblot assay and distributed in both cytoplasm and nucleus of host cell in immunofluorescent (IF) staining test. bcSIKE showed no IFN-inducing ability in reporter assay and EPC cells expressing bcSIKE showed no enhanced antiviral ability against either grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV). However, bcSIKE obviously dampened the IFN-inducing ability of RLR signaling members in reporter assay when bcSIKE was co-expressed with these molecules in EPC cells. The association between bcSIKE and bcTBK1 has been identified through IF and co-immunoprecipitation (co-IP) assay. The plaque assay demonstrated clearly that bcTBK1-mediated antiviral activity in EPC cells against both GCRV and SVCV was down regulated by bcSIKE. All the data generated in this paper support the conclusion that bcSIKE interacts with bcTBK1 and inhibits bcTBK1-mediated antiviral signaling during host innate immune activation, which is reported in teleost for the first time.

TBK1 of black carp plays an important role in host innate immune response against SVCV and GCRV.

Tank-binding kinase 1 (TBK1) plays a pivotal role in the induction of type I IFNs in higher vertebrates. To explore the function of TBK1 in teleost, TBK1 of black carp (Mylopharyngodon Piceus) was cloned and characterized in this paper. The full-length cDNA of black carp TBK1 (bcTBK1) consists of 2857 nucleotides and the predicted bcTBK1 protein contains 727 amino acids, which includes an N-terminal kinase domain (KD), an ubiquitin-like domain (ULD) and two C-terminal coiled-coils. The transcription of bcTBK1 was constitutively detected in all the selected tissues and bcTBK1 mRNA level was increased in all selected tissues in response to SVCV or GCRV infection except that in muscle post GCRV invasion. The transcription of bcTBK1 in Mylopharyngodon Piceus fin (MPF) cells was up-regulated by the stimulation of SVCV, GCRV or poly (I:C) but not by LPS treatment. bcTBK1 migrated around 80 kDa in immunoblot assay and was identified as a cytosolic protein by immunofluorescence staining. bcTBK1 showed strong IFN-inducing ability in reporter assay and presented strong antiviral activity against both GCRV and SVCV in EPC cells. The reporter assay demonstrated that TRAF6 of black carp (bcTRAF6) up-regulated bcTBK1-induced IFN expression and the subcellular distribution of bcTBK1 overlapped with that of bcTRAF6 when these two proteins were co-expressed in EPC cells. Taken together, our study support the conclusion that bcTBK1 plays an important role in the antiviral innate immune response of black carp against SVCV and GCRV, in which its activity was positively regulated by bcTRAF6.

CARD and TM of MAVS of black carp play the key role in its self-association and antiviral ability.

Mitochondrial antiviral signaling protein (MAVS) is an adaptor protein of the innate immune system of higher vertebrate. In this paper, the transcription profile of black carp MAVS (bcMAVS) in host cells in response to spring viremia of carp virus (SVCV) and grass carp reovirus (GCRV) infection was identified. EPC cells expressing bcMAVS possessed obviously enhanced antiviral activity against both SVCV and GCRV. Immunofluorescence (IF) staining data demonstrated that bcMAVS molecules were redistributed and formed aggregates on the mitochondria of EPC cells after virus infection. Co-immunoprecipitation (co-IP) assay in HEK293T cells demonstrated that bcMAVS proteins bound to each other, which suggested that this fish protein owned self-association in vivo. IF assay identified that the transmembrane (TM) domain of bcMAVS was crucial for its mitochondrial localization. Co-IP assays among bcMAVS mutants demonstrated that both N-terminal caspase recruitment domain (CARD) and TM domain were indispensible for dimerization of bcMAVS. It was interesting that Truncated-bcMAVS possessed much enhanced interferon-inducing activity and antiviral ability than wild type bcMAVS, which only contains CARD and TM. All the data generated in this study support the idea that oligomerization of bcMAVS on mitochondrion is crucial for the antiviral ability of bcMAVS, which is depend on both CARD and TM domain of this fish MAVS orthologue.