Tumor-infiltrating B cells and intratumorally-produced immunoglobulins (IG) play important roles in the tumor microenvironment and response to immunotherapy. IgG antibodies produced by intratumoral B cells may drive antibody-dependent cellular cytotoxicity (ADCC) and enhance antigen presentation by dendritic cells. Furthermore, B cells are efficient antigen-specific antigen presenters that can essentially modulate the behaviour of helper T cells. Here we investigated the role of intratumoral IG isotype and clonality in bladder cancer. Our results show that the IgG1/IgA ratio offers a strong and independent prognostic indicator for the Basal squamous molecular subtype and for the whole ImVigor210 cohort in anti-PD-L1 immunotherapy. Our findings also indicate that effector B cell functions, rather than clonally-produced antibodies, are involved in the antitumor response. High IgG1/IgA ratio was associated with relative abundance of cytotoxic genes and prominence of the IL-21/IL-21R axis suggesting importance of T cell/B cell interaction. We integrated the B, NK, and T cell components, employing immFocus-like normalization to account for the stochastic nature of tumor tissue sampling. Using a random forest model with nested cross-validation, we developed a tumor RNA-Seq-based predictor of anti-PD-L1 therapy response in muscle-invasive urothelial carcinoma. The resulting PRIMUS (PRedIctive MolecUlar Signature) predictor achieves superior sensitivity compared to PD-L1 expression scores or existing gene signatures, allowing for reliable identification of responders even within the desert patient subcohort analyzed as a hold out set.

中文翻译：

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考虑到B细胞行为和采样偏倚可产生膀胱癌中抗PD-L1反应的出色预测指标

肿瘤浸润性B细胞和肿瘤内产生的免疫球蛋白（IG）在肿瘤微环境和对免疫疗法的反应中起重要作用。肿瘤内B细胞产生的IgG抗体可能会驱动抗体依赖性细胞毒性（ADCC），并增强树突状细胞的抗原呈递。此外，B细胞是有效的抗原特异性抗原呈递剂，可实质上调节辅助T细胞的行为。在这里，我们调查了肿瘤内IG同种型和克隆性在膀胱癌中的作用。我们的结果表明，IgG1 / IgA比为抗PD-L1免疫治疗中的基底鳞状亚型和整个ImVigor210队列提供了强大而独立的预后指标。我们的发现还表明，效应子B细胞的功能而不是克隆产生的抗体，参与抗肿瘤反应。较高的IgG1 / IgA比例与细胞毒性基因的相对丰度和IL-21 / IL-21R轴的突出有关，提示T细胞/ B细胞相互作用的重要性。我们整合了B，NK和T细胞成分，并采用类似immFocus的归一化方法来说明肿瘤组织采样的随机性。使用具有嵌套交叉验证的随机森林模型，我们开发了基于肿瘤RNA-Seq的抗PD-L1治疗反应的肌肉浸润性尿路上皮癌预测因子。与PD-L1表达评分或现有基因签名相比，所得的PRIMUS（预测分子签名）预测因子可实现更高的灵敏度，即使在作为分析集的沙漠患者亚组中也可以可靠地鉴定响应者。较高的IgG1 / IgA比例与细胞毒性基因的相对丰度和IL-21 / IL-21R轴的突出有关，提示T细胞/ B细胞相互作用的重要性。我们整合了B，NK和T细胞成分，并采用类似immFocus的归一化方法来说明肿瘤组织采样的随机性。使用具有嵌套交叉验证的随机森林模型，我们开发了基于肿瘤RNA-Seq的抗PD-L1治疗反应的肌肉浸润性尿路上皮癌预测因子。与PD-L1表达评分或现有基因签名相比，所得的PRIMUS（预测分子签名）预测因子可实现更高的灵敏度，即使在作为分析集的沙漠患者亚组中也可以可靠地鉴定响应者。较高的IgG1 / IgA比例与细胞毒性基因的相对丰度和IL-21 / IL-21R轴的突出有关，提示T细胞/ B细胞相互作用的重要性。我们整合了B，NK和T细胞成分，并采用类似immFocus的归一化方法来说明肿瘤组织采样的随机性。使用具有嵌套交叉验证的随机森林模型，我们开发了基于肿瘤RNA-Seq的抗PD-L1治疗反应的肌肉浸润性尿路上皮癌预测因子。与PD-L1表达评分或现有基因签名相比，所得的PRIMUS（预测分子签名）预测因子可实现更高的灵敏度，即使在作为分析支持集的沙漠患者亚组中，也可以可靠地鉴定响应者。