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Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell-inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase- 2, lies downstream of EPHA2 signaling through TGF-[beta] and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-[beta]/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma., Introduction Immunotherapies, including immune checkpoint blockade (ICB), have led to significant improvement of clinical care for cancer patients (1-4). Patients with melanoma, lung adenocarcinoma, or kidney cancer have a 20%-40% [...]

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Tribl ([Trib1.sup.[DELTA]hep]) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBP[alpha]) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of [Trib1.sup.[DELTA]hep] but not [Trib1.sup.[DELTA]hep] [Cebpa.sup.[DELTA]hep] mice. ATF3 has been shown to directly bind to the CEBP[alpha] protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in [Trib1.sup.[DELTA]hep] mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBP[alpha], which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C., Introduction The TRIB1 gene, which encodes Tribbles homolog 1 protein (TRIB1), has been suggested as the causal effector transcript underlying the genome-wide association study (GWAS) signal at human chromosomal locus [...]

Androgenetic alopecia (AGA), also known as common baldness, is characterized by a marked decrease in hair follicle size, which could be related to the loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from AGA individuals for the presence of hair follicle stem and progenitor cells. Cells expressing cytokeratin15 (KRT15), CD200, CD34, and integrin, α6 (ITGA6) were quantitated via flow cytometry. High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. These [KRT15.sup.hi] stem cells were maintained in bald scalp samples. However, [CD200.sup.hi][ITGA6.sup.hi] and [CD34.sup.hi] cell populations--which both possessed a progenitor phenotype, in that they localized closely to the stem cell-rich bulge area but were larger and more proliferative than the KRT15hi stem cells--were markedly diminished. In functional assays, analogous [CD200.sup.hi][Itga6.sup.hi] cells from murine hair follicles were multipotent and generated new hair follicles in skin reconstitution assays. These findings support the notion that a defect in conversion of hair follicle stem cells to progenitor cells plays a role in the pathogenesis of AGA., Introduction Adult somatic stem cells act as the ultimate source of cells for self-renewing epithelia during homeostasis and wound healing. In the skin, a portion of the hair follicle known [...]

Nonstandard abbreviations used: BCR, B cell receptor; DLBCL, diffuse large B cell lymphoma; ITAM, immunoreceptor tyrosine-based activation motif; 4OHT, 4-hydroxytamoxifen; Pax5ERTAM, fusion of Pax5 and tamoxifen receptor; shRNA, short hairpin [...]