课程文献中心 更多>>

关键词： Melanoma   Il-2 liposome   Sorafenib   Tumor immunotherapy   Synergistic immunotherapy   Nanoliposome   M1/m2 macrophage polarization   Anti-angiogenic therapy  

摘要： Immunotherapy with interleukin-2 (IL-2) in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise. To address these challenges, IL-2-So-Lipo, a novel liposomal formulation combining IL-2 with sorafenib derivative, was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth. Sorafenib derivatives could target at melanoma-specific receptors, further enhancing liposomal specificity at the tumor site. Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies, as well as their combination. In a B16F10 melanoma model, IL-2-So-Lipo was found to significantly inhibit tumor progression (tumor volume of 108.01 f 62.99 mm3 ) compared to the control group (tumor volume of 1,397.13 f 75.55 mm3 ), improving the therapeutic efficacy. This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes. Additionally, liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency, promoting tumor cell apoptosis and suppressing angiogenesis. Mechanistically, IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype. Furthermore, IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway, exerting a significant role in mediating tumor resistance to sorafenib. These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers. Moreover, the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy, offering a synergistic approach to improve therapeutic

摘要： Host effector CD4(+) T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8(+) T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8(+) T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4(+) T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4(+) T cells against relapsed tumors. Host CD4(+) T cell or cDC2 deficiency impaired the ability of Tc9 cells to control relapsed tumor outgrowth. Additionally, intratumoral IL24 expression correlates with cDC2 and CD4(+) T cell gene signatures in human cancers and their expression is associated with better patient survival. This study reports a mechanism for activation of tumor-specific CD4(+) T cells in vivo.

关键词： allo-HCT   GVHD   MMUD   overall survival   progression-free survival   PTCY-based prophylaxis  

摘要： Although post-transplant cyclophosphamide (PTCY)-based prophylaxis has become a widely adopted strategy for preventing graft-versus-host disease (GVHD) in 9 out of 10 HLA-mismatched unrelated donors (MMUDs), allogeneic hematopoietic cell transplants (allo-HCTs), data on the safety and efficacy of PTCY in this setting remain limited. This single-center study investigates the outcomes of 94 adults with hematological malignancies undergoing MMUD allo-HCT with PTCY and tacrolimus (Tac) (PTCY-Tac) between 2014 and 2023. The median age was 53 years, and 60.6% were male. Peripheral blood stem cells were infused in all cases. By Day +100, the cumulative incidence of Grades II-IV and Grades III and IV acute GVHD were 33.0% and 9.7%, with 2-year incidence of moderate-to-severe chronic GVHD at 12.6%. By Day +30, 40.8% of patients experienced bacterial bloodstream infections, and 52.4% had cytomegalovirus (CMV) reactivation before letermovir prophylaxis. With letermovir's introduction, CMV reactivation rates dropped significantly, with only one case reported. At 3 years, overall survival was 60.8%, non-relapse mortality was 23%, and the cumulative incidence of relapse was 24.5%. HLA Class I or II mismatches did not affect key outcomes or GVHD rates. These findings demonstrate that PTCY-Tac offers effective GVHD prevention and favorable outcomes in MMUD allo-HCT, supporting its application for patients without fully matched donors.

关键词： Chechen   HLA-B*35:636N   NGS   novel allele  

摘要： Characterisation of the novel HLA-B*35:636N allele in two bone marrow donors from the Russian State Registry.

摘要： Takayasu arteritis, a granulomatosis vasculitis with a pathogenesis that is poorly defined but known to be associated with HLA-B*52, shares many features with other MHC-I-opathies. In addition to the shared clinical features of inflammatory bowel diseases, cutaneous inflammation, and HLA-B*52, is shared association of an IL12B singlenucleotide polymorphism encoding the common IL-12 and IL-23 p40 subunit, which might affect not only type 17 cytokine responses, but also IFN gamma and TNF production-the cardinal type 1 cytokines in granuloma formation. Considering the translational context of responses to TNF inhibition in Takayasu arteritis, in this Personal View we propose Takayasu arteritis as a type 1 MHC-I-opathy. Additionally, type 1 and type 17 T-cell immune responses show immune plasticity, which connects the overlapping features of Takayasu arteritis and spondyloarthritis spectrum disorders, providing a basis for shared anti-TNF responses, and points to p40 and IFN gamma cytokine antagonism and potential selective CD8 T-cell repertoire ablation.

关键词： domestication   MHC   artificial selection   aquaculture   ohnolog  

摘要： Domestication and artificial selection for desirable traits have driven significant phenotypic changes and left detectable genomic footprints in farmed animals. Since the 1960s, intensive breeding has led to the rapid domestication of Atlantic salmon (Salmo salar), with multiple independent events that make it a valuable model for studying early domestication stages and the parallel evolution of populations of different origins subjected to similar selection pressures. Some aquatic species, including Atlantic salmon, have undergone whole-genome duplication (WGD), raising the possibility that genetic redundancy resulting from WGD has contributed to adaptation in captive environments, as seen in plants. Here, we examined the genomic responses to domestication in Atlantic salmon, focusing on potential signatures of parallel selection, including those associated with WGD. Candidate genomic regions under selection were identified by comparing whole-genome sequences from aquaculture and wild populations across 2 independently domesticated lineages (Western Norway and North America) using a genome-wide scan that combined 3 statistical methods: allele frequencies (FST), site frequency (Tajima's D), and haplotype differentiation (XP-EHH). These analyses revealed shared selective sweeps on identical SNPs in major histocompatibility complex (MHC) genes across aquaculture populations. This suggests that a combination of long-term balancing selection and recent human-induced selection has shaped MHC gene evolution in domesticated salmon. Additionally, we observed selective sweeps on a small number of gene pairs in homeologous regions originating from WGD, offering insights into how historical genome duplication events may intersect with recent selection pressures in aquaculture species.