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Vitiligo is an acquired autoimmune skin disorder, clinically characterized by distinct white macules and patches resulting from progressive melanocyte destruction. JAK-STAT pathway plays an important role in the loss of epidermal melanocytes. Baricitinib can block the JAK-STAT pathway and the downstream chemokines as a new JAK1/2 inhibitor. In this report, we describe the successful treatment of 2 patients with oral baricitinib combined with NB-UVB phototherapy, which provides a good alternative and supplementary to treat refractory vitiligo. [ABSTRACT FROM AUTHOR]

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4 + T and CD8 + T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-γ (IFN-γ) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-γ-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5–7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by in silico bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST.

Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5–7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by in silico bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST. [ABSTRACT FROM AUTHOR]

Few studies were conducted investigating the immunological profiles in gastrointestinal stromal tumors (GIST). Adaptive and innate immune cells are present in the tumor microenvironment, indicating GIST as inflamed tumors. In addition, murine models suggested a potential interaction between immune components and imatinib. In this retrospective study, the GIST immunological profile was investigated through in silico analysis and immunohistochemistry (IHC), exploring the basis for immunotherapy approaches. Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS). GEP and IHC supported the presence of immune infiltrate in GIST, with dominance of CD4+ and CD8+ T cells and M2 macrophages showing a remarkable similarity with melanoma microenvironment. The EIIS genes were expressed in most of GIST samples and positively correlated with PD-L1 abundance (p

Few studies were conducted investigating the immunological profiles in gastrointestinal stromal tumors (GIST). Adaptive and innate immune cells are present in the tumor microenvironment, indicating GIST as inflamed tumors. In addition, murine models suggested a potential interaction between immune components and imatinib. In this retrospective study, the GIST immunological profile was investigated through in silico analysis and immunohistochemistry (IHC), exploring the basis for immunotherapy approaches. Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS). GEP and IHC supported the presence of immune infiltrate in GIST, with dominance of CD4+ and CD8+ T cells and M2 macrophages showing a remarkable similarity with melanoma microenvironment. The EIIS genes were expressed in most of GIST samples and positively correlated with PD-L1 abundance (p <.0001). Co-expression was also found between PD-L1 and CD8A (p <.0001) or CD8B (p =.0003). Moreover, the median TIS score for GIST was between the 65th and 70th percentile of the Cancer Genome Atlas dataset, in the same range of tumors responding to anti-PD-1/PD-L1. Analysis of the Gene Expression Omnibus database GIST samples pre- and post-treatment confirmed that imatinib downregulates PD-L1 and IRF1 expression through the inhibition of KIT and PDGFRA, thus contributing to counteract the suppressed adaptive immune response against GIST. The presence of a rich immune infiltrate in GIST along with the presence of TIS and EIIS suggests that GIST may benefit from immunotherapy along with tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

The benefits of IL2RA antagonists in heart transplant patients are controversial. We aimed to elucidate the effects of IL2RA antagonists and identify targets that could be better than IL2RA antagonists. By using single-cell RNA sequencing of immune cells at different time points in patients receiving IL2RA antagonists, we identified nineteen types of cells. We revealed higher IL2RA expression in regulatory T cells (Tregs), suggesting that IL2RA antagonists attenuated IL-2-induced Treg activation. CD4_C04_IFNGR1 and CD8_C05_IFITM2 which had more cytotoxic effects, remained elevated at later time points. IFNGR1 was upregulated in these two subtypes, but was not expressed in Treg. Ruxolitinib targeted the pathways of IFNGR1 (JAK1/2) while not affecting the pathway of IL-2-induced Tregs activation (JAK3). Ruxolitinib showed prolonged survival compared to IL2RA mAb-treated mice. Our study provided dynamic changes of immune cells after IL2RA antagonists treatment at single-cell resolution. Ruxolitinib has potential as a new immunoinduction therapy without affecting Treg. [ABSTRACT FROM AUTHOR]

Abstract: Based on the fact that the transcription of STAT-1 plus its Serine 727 and Tyrosine 701 phosphorylation is not the pre-requisite for the cell death signal transduction in the IFN-γ signaling pathway induced by co-immobilized IFN-γ/TNF-α, we investigate both in vitro and in vivo the key transcription regulators to promote the signal transduction of HeLa cells. It is found that IFN-γ R2 is the important death signal receptor in the HeLa cell death by RNA interference. Checking the expression of the whole transcription (STAT) protein family reveals that STAT-6 is highly expressed in comparison with the other STAT proteins. The gene silence of IFN-γ R2 leads to the down-regulation of STAT-6 and phosphorylation-STAT-6 (p-STAT-6) expressions. The successful gene silence of STAT-6 results in the reduction of HeLa cell programmed death and the expression of several important key factors related to programmed cell death (p53, Bcl-2, and Bax). More importantly, our in vivo experiments by injecting nanoparticle drug carriers with the co-immobilized IFN-γ/TNF-α into nude mice model confirm the high expression of STAT-6 and p-STAT-6. It is thus concluded that, in response to IFN-γ, the co-immobilized IFN-γ/TNF-α unusually promotes the activation of STAT-6 rather than STAT-1, resulting in the enhanced cell programmed death in HeLa. The present work reveals the gene-level molecular mechanism of IFN-γ/TNF-α co-immobilized on biomaterials as a potentially effective therapy against cancer cells. [Copyright &y& Elsevier]

Abstract: Interferon-γ (IFN-γ) plays a pathogenic role in systemic lupus erythematosus (SLE). Uncontrolled IFN-γ signaling may result from a deficiency in the negative regulator, namely, suppressor of cytokine signaling-1 (SOCS-1). We investigated the activation status of IFN-γ signaling pathway in SLE-afflicted (New-Zealand-Black×New-Zealand-White)F1 mice and determined its responsiveness when treating with a tolerogenic peptide, hCDR1, which ameliorates SLE. SOCS-1 was suppressed and pSTAT1 was enhanced in spleen-derived cells from SLE-affected mice as compared with healthy controls. Treatment with hCDR1 reversed the expression of these two molecules in association with clinical amelioration. In vitro stimulation with IFN-γ resulted in elevated levels of SOCS-1 in cells from both vehicle and hCDR1-treated mice but this effect reached significance only in cells of the latter group, which also exhibited reduced levels of pSTAT1. Thus, SOCS-1 is diminished in SLE-affected mice, and treatment with hCDR1 results in its up-regulation thereby restoring control of IFN-γ signaling pathway. [Copyright &y& Elsevier]