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关键词： HIV   T cells   HLA-B∗57:01   HIV controller   TW10 epitope   T cell receptor recognition   crystal structure   CP: Immunology  

摘要： HIV controllers can control viral replication and remain healthy, but the mechanism behind this control is unknown. Despite human leukocyte antigen (HLA) diversity in the population, almost 50% of HIV controllers express the HLA-B*57:01 molecule, which presents, among others, the Gag-derived epitope TW10. Given TW10's presentation in early infection, TW10-specific T cells could participate in the control of HIV. Here, we study the strength and functionality of TW10-specific T cells from HLA-B*57:01+/HIV+ + /HIV + controller and non-controller individuals. We determine the TW10-specific T cell receptor (TCR) repertoire, revealing a bias in TCR gene usage with the presence of a public TCR. We determine that the T cell response is polyfunctional regardless of the viral load, despite the low affinity of TW10-specific TCRs. We solve the crystal structure of HLA-B*57:01-TW10 in complex with a TCR, providing the basis of recognition that underpins the strong TRBV5 bias observed in TW10-specific clonotypes.

摘要： IL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37+/ST2L+/CD206+ tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer.

关键词： IL-12/23 inhibitors   IL-17 inhibitors   personalized treatment   TNF inhibitors  

摘要： Whether clinical and genetic markers can be used to differentiate patients with varying responses to different psoriasis therapies needs to be elucidated. Here, we assess whether human leukocyte antigen C (HLA-C)*06:02 is associated with response to biologics. Response to treatment was defined as a Psoriasis Area and Severity Index score of <= 2 (PASI <= 2) after 3 months. In total, 648 patients with psoriasis initiating treatment with biologics were included;289 were HLA-C*06:02 positive and 359 were HLA-C*06:02 negative. Patients were treated with tumor necrosis factor (TNF) inhibitors (n = 469), interleukin (IL)-12/23 inhibitors (n = 92), IL-17 inhibitors (n = 78), and IL-23 inhibitors (n = 9). Significantly more patients positive for HLA-C*06:02 achieved PASI <= 2 compared with patients negative for HLA-C*06:02 when treated with IL-12/23 inhibitors. There was no significant difference between response in HLA-C*06:02 positive and negative patients for TNF inhibitors or IL-17 inhibitors. No analyses were conducted for IL-23 inhibitors because of the limited number of patients. The data confirm that HLA-C*06:02 may be used as a biomarker for response to anti-IL12/23 treatment.

摘要： Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B;however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8+ T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1 -> S phase-transition block. These mutant CD8+ T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2R beta and IL-2R gamma. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8+ T cells. The importance of STAT5 tyrosine phosphorylation on T cells has not been investigated in vivo. Here the authors generate STAT5A and STAT5B tyrosine mutant knockin mice and show that Stat5a/b tyrosine is required for maximal IL-2 signaling and CD8 + T cell proliferation.

关键词： CP: Immunology   CP: Cancer  

摘要： HMGB1 (high-mobility group box-1) has been extensively studied as a damage-associated molecular pattern, with secreted cytokine function. However, its regulation on T cells, especially the function in the nucleus, has not been elucidated. Here, we use conditional knockout (HMGB1-f/f;CD2-cre) mice and find that HMGB1 potentiates the proliferation and interferon gamma (IFN-y) expression of CD8 T cells rather than CD4 T cells. Notably, nuclear, but not secreted, HMGB1 supports the expression of IFN-y in CD8 T cells via directly regulating the activity of Eomes, the transcription factor for IFN-y. Functional study shows that HMGB1 promotes the anti-tumor ability of CD8 T cells in vitro and in vivo. . Finally, tumor environmental interleukin-7 promotes HMGB1 and IFN-y production via fatty acid oxidation in CD8 T cells. Overall, we identify the role of nuclear HMGB1 in CD8 T cell differentiation and demonstrate that it plays an important role in the anti-tumor programs of CD8 T cells.

关键词： 肾癌   衍生的中性粒细胞淋巴细胞比值   肺免疫预后指数   预后  

摘要： 目的 探讨衍生的中性粒细胞淋巴细胞比值（dNLR）和肺免疫预后指数（LIPI）对靶向药物联合免疫检查点抑制剂（ICIs）治疗晚期肾癌患者预后的影响。方法 回顾性收集2020年3月至2024年2月于新疆医科大学附属肿瘤医院接受靶向联合ICIs治疗的65例晚期肾癌患者的临床资料。根据治疗前血常规结果计算出dNLR值，采用受试者工作特征（ROC）曲线确定最佳dNLR截断值，根据截断值将患者分为低dNLR水平组（n=36）和高dNLR水平组（n=29）。根据治疗前乳酸脱氢酶（LDH）值和dNLR二者的组合得出LIPI评分，将患者分为LIPI优组(n=44)和LIPI中/差组（n=21）。使用Kaplan-Meier方法进行生存分析，并进行Log-Rank检验，采用Cox风险比例回归模型对预后影响因素进行分析。结果dNLR预测晚期肾癌患者预后的最佳截断值为2.57（AUC=0.729）。低dNLR水平组患者总生存率显著高于高dNLR水平组；LIPI优组总生存率显著高于LIPI中/差组。单因素分析结果显示，国际转移性肾细胞癌数据库联盟危险分层（IMDC）评分、体重指数（BMI）、dNLR、LDH、LIPI、淋巴结转移与患者预后均具有相关性（P<0.05）。多因素分析结果显示，IMDC、dNLR、LIPI为患者预后的独立影响因素（HR＞1，P＜0.05）。结论 dNLR水平和LIPI评分与接受靶向联合ICIs治疗晚期肾癌患者的预后有相关，治疗前高dNLR水平以及较差LIPI评分提示晚期肾癌患者的预后较差。

关键词： IL-33   ST2   Optic nerve injury   Retinal neurodegeneration   Astrocyte   Neuroprotection  

摘要： IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33-/- and WT mice after ON injury, but not in ST2-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.

关键词： 黏膜黑色素瘤   淋巴细胞免疫分型   细胞因子   免疫联合抗血管生成治疗  

摘要： 目 的：探讨晚期黏膜黑色素瘤患者免疫联合抗血管生成治疗前后外周血淋巴细胞免疫分型、细胞因子水平和治疗效果及预后的相关性。方 法：纳入分析2019年4月至2022年6月在南京大学医学院附属鼓楼医院收治的28例晚期黏膜黑色素瘤患者，所有患者均接受卡瑞利珠单抗（PD-1抑制剂）及甲磺酸阿帕替尼（抗血管生成药物）的联合治疗，采集患者治疗前、2周期治疗后外周血，进行淋巴细胞免疫分型、细胞因子水平检测，评估与治疗效果及患者预后的相关性。结 果：黏膜黑色素瘤患者接受卡瑞利珠单抗联合甲磺酸阿帕替尼治疗2周期后，外周血PD-1阳性细胞毒性T淋巴细胞(CD3+CD8+CD279+细胞)比例显著降低，治疗响应的患者有明显的NK细胞(CD3-CD16+CD56+细胞)比例的提升，较无响应的患者差异有统计学意义。治疗前外周血IFN-γ水平与OS相关，HR为0.28，IFN-γ低水平的患者中位OS为329天，高水平的患者中位OS未达到。基线期IFN-γ水平越高，PFS倾向获益越大。结 论：患者外周血PD-1阳性T淋巴细胞比例、NK细胞比例、IFN-γ水平对接受免疫联合抗血管生成治疗的晚期黏膜黑色素瘤患者的疗效及预后可能有预测价值，未来仍需要大样本研究以更好的表征临床应用潜力。

关键词： lysophosphatidic acid (LPA)   melanoma   death receptor 6 (DR6)   IL-10   LPAR1   HLA-DR  

摘要： While immune checkpoint inhibitors (ICIs) are promising in the treatment of metastatic melanoma, about half of patients do not respond well to them. Low levels of human leukocyte antigen-DR (HLA-DR) in tumors have been shown to negatively influence prognosis and response to ICIs. Lysophosphatidic acid (LPA) is produced in large amounts by melanoma and is abundantly present in the tumor microenvironment. LPA induces the release of various cytokines and chemokines from tumor cells, which affect cancer development, metastasis, and tumor immunity. In the present study, we investigated the role of LPA-induced IL-10 release in regulating HLA-DR expression and the underlying mechanisms in human melanoma cells. We showed that LPA (0.001-10 mu M) dose-dependently increased DR6 transcript levels through activating LPAR1 in HEK293T cells. Knockdown of NF-kappa B1 abrogated the LPA-increased DR6 expression without affecting basal DR6 expression in both A2058 and A375 melanoma cell lines. LPA (10 mu M) significantly increased IL-10 transcripts in A2058 and A375 melanoma cells, the effect was abolished by pharmacological inhibition of LPAR1 or knockdown of DR6. We found a statistically significant correlation between the expression of LPAR1, DR6 and IL-10 in human melanoma tissue and an association between increased expression of LPAR1 and reduced effectiveness of ICI therapy. We demonstrated that LPA (10 mu M) markedly suppressed HLA-DR expression in both A375 and A2058 melanoma cells via activating the LPAR1-DR6-IL-10 pathway. These data suggest that the LPAR1-DR6-IL-10 autocrine loop could constitute a novel mechanism used by tumor cells to evade immunosurveillance by decreasing HLA-DR expression.