Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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不同严重程度鼻炎患者尘螨舌下特异性免疫治疗临床效果观察

目的　评估不同严重程度变应性鼻炎（allergic rhinitis，AR）患儿进行规范化舌下特异性免疫治疗（sublingual immunotherapy， SLIT）的疗效。方法　选取2017年5—12月首都儿科研究所附属儿童医院耳鼻喉科就诊的3～14岁对粉尘螨过敏的AR患儿181例， 按治疗方式不同分为对照组（n＝92， 给予常规药物治疗）和SLIT组（n＝89， 给予尘螨特异性免疫治疗）； 采用AR评分标准， 根据患儿鼻部症状总评分（total nasal symptoms score， TNSS）， 将对照组分为轻度组（n＝35）、中度组（n＝28）和重度组（n＝29）；将SLIT分为轻度组（n＝27）、中度组（n＝33）和重度组（n＝29）。收集第6个月、 1年、 2年的随访数据， 分别对患儿进行TNSS、 鼻炎用药评分（total rhinitis medication scores， TRMS）和视觉模拟量表（visual analogue scale，VAS）评分。结果　（1）治疗2年后， SLIT组与对照组患儿TNSS评分分别为0.61±0.73、 1.61±1.17， TRMS分别为0.21±0.41、 0.59±0.70， VAS分别为0.63±0.70、 1.53±1.24， 两组间差异有统计学意义， Z值分别为6.269、 4.139、5.174， P值均＜0.05； （2）轻度组（n＝62）组内分析： SLIT组（n＝27）与对照组（n＝35）比较， 治疗6个月、 1年， 两组的TNSS、 TRMS、 VAS差异均无统计学意义（Z值分别为-0.108、 0.232、 0.788， 0.774、 0.033、 -0.718； P值均＞0.05）； 治疗2年时两组的TRMS、 VAS差异无统计学意义（Z值分别为0.230、 1.255， P＞0.05）， TNSS在两组间差异有统计学意义（Z值为2.528， P值均＜0.05）； （3）中度组（n＝61）组内分析： 与对照组（n＝28）比较， SLIT组（n＝33）治疗6个月， TRMS、 VAS在两组间差异均无统计学意义（Z值分别为-0.413、 0.412， P值均＞0.05）， 但两组的TNSS差异有统计学意义（Z值为2.397， P＜0.05）； 治疗1年、2年的TNSS、 TRMS、 VAS两组间比较， 差异均有统计学意义（Z值分别为4.952、 2.740、 3.293； 4.743、 2.505、 3.330； P值均＜0.05）； （4）重度组（n＝58）组内分析： 与对照组（n＝29）比较， SLIT组（n＝29）治疗6个月、 1年、 2年的TNSS、 TRMS、 VAS在两组间差异均有统计学意义（Z值分别为2.567、 2.086、 2.781， 4.996、 4.264、 2.756， 4.253、 4.480、 4.515， P值均＜0.05）。结论　采用标准化粉尘螨滴剂舌下治疗尘螨致敏AR患儿， 治疗2年可获得较单纯药物治疗更佳的疗效， 尤其在病情严重患儿，其获益更大。     

Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity

The T cell co-stimulatory molecule OX40 and its cognate ligand OX40L have attracted broad research interest as a therapeutic target in T cell-mediated diseases. Accumulating preclinical evidence highlights the therapeutic efficacy of both agonist and blockade of the OX40–OX40L interaction. Despite this progress, many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered. In this review we summarize the impact of the OX40–OX40L interaction on T cell subsets, including Th1, Th2, Th9, Th17, Th22, Treg, Tfh, and CD8⁺ T cells, to gain a comprehensive understanding of anti-OX40 mAb-based therapies. The potential therapeutic application of the OX40–OX40L interaction in autoimmunity diseases and cancer immunotherapy are further discussed; OX40–OX40L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases. We also explore the rationale of targeting OX40–OX40L interactions in cancer immunotherapy. Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells. When combined with other therapeutic treatments, such as anti-PD-1 or anti-CTLA-4 blockade, cytokines, chemotherapy, or radiotherapy, the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced. These data collectively suggest great potential for OX40-mediated therapies.     

Racial differences in characteristics and prognoses between Asian and white patients with nonsmall cell lung cancer receiving atezolizumab: An ancillary analysis of the POPLAR and OAK studies

This study aimed to compare the differences in characteristics and prognoses between Asian and white patients receiving immunotherapy for nonsmall cell lung cancer (NSCLC). We studied 390 patients who received atezolizumab as part of the POPLAR or OAK trial, and analyzed the differences in baseline characteristics, outcomes and genetic mutations in blood samples between Asian and white patients. Overall survival (OS) was longer in Asian compared to white patients (median OS: 18.7 vs. 11.1 months; p = 0.005). Race was identified as an independent prognostic factor for OS (Asian vs. white: hazard ratio 0.647, 95% confidence interval 0.447–0.936, p = 0.021), together with performance status, histology, baseline sum of the longest tumor diameters (BLSLD) and number of metastatic sites. The two groups also differed in terms of characteristics including smoking history, BLSLD, epidermal growth factor receptor (EGFR) mutation frequency, programmed death-ligand 1 expression and blood-based tumor-mutation burden. Blood mutations of STK11, EGFR, KEAP1, POLE, GRM3, ATM and STAG2 were associated with treatment response, and TP53, KEAP1, APC, RB1, CREBBP, EPHA5 and STAG2 mutations were associated with OS. The blood-based mutation profiles differentiated between Asian and white patients, especially in relation to EGFR (23.8 vs. 8.5%), TP53 (30.2 vs. 46.9%) and STK11 (1.6 vs. 12.3%) mutations (all p < 0.05). The different clinicopathological features and mutation profiles in Asian and white patients may explain the superior outcome following atezolizumab treatment in Asian patients with NSCLC. The results of this study have important implications for further studies on racial disparities in relation to immunotherapy.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.