Induced B7-H1 expression in the tumor microenvironment initiates adaptive resistance, which impairs immune functions and leads to tumor escape from immune destruction. Antibody blockade of the B7-H1/PD-1 interaction overcomes adaptive resistance, leading to regression of advanced human cancers and survival benefits in a significant fraction of patients. In addition to cancer cells, B7-H1 is expressed on dendritic cells (DCs), but its role in DC functions is less understood. DCs can present multiple antigens (Ags) to stimulate dominant or subdominant T cell responses. Here, we show that immunization with multiple tumor Ag-loaded DCs, in the absence of B7-H1, vastly enhances cytotoxic T lymphocyte (CTL) responses to dominant Ag. In sharp contrast, CTL responses to subdominant Ag were paradoxically suppressed, facilitating outgrowth of tumor variants carrying only subdominant Ag. Suppressed CTL responses to subdominant Ag are largely due to the loss of B7-H1–mediated protection of DCs from the lysis of CTL against dominant Ag. Therefore, B7-H1 expression on DCs may help maintain the diversity of CTL responses to multiple tumor Ags. Interestingly, a split immunization approach, which presents dominant and subdominant Ags with different DCs, promoted CTL responses to all Ags and prevented tumor escape in murine tumor models. These findings have implications for the design of future combination cancer immunotherapies.

在肿瘤微环境中诱导的B7-H1表达引发适应性抗性，从而削弱免疫功能并导致肿瘤逃避免疫破坏。抗体对B7-H1 / PD-1相互作用的阻断克服了适应性耐药，导致晚期人类癌症消退，并在相当一部分患者中提高了生存率。除了癌细胞外，B7-H1还可以在树突状细胞（DC）上表达，但其在DC功能中的作用尚不清楚。DC可以呈递多种抗原（Ags），以刺激显性或显性T细胞反应。在这里，我们显示了在没有B7-H1的情况下，用多个装有肿瘤Ag的DC进行的免疫大大增强了对主要Ag的细胞毒性T淋巴细胞（CTL）反应。与之形成鲜明对比的是，CTL对主要Ag的反应被反常抑制，促进仅携带主要Ag的肿瘤变体的生长。对次要Ag抑制的CTL反应很大程度上是由于B7-H1介导的CTL裂解而对主要Ag失去了对DC的保护。因此，DC上的B7-H1表达可能有助于维持对多种肿瘤Ag的CTL反应的多样性。有趣的是，在鼠类肿瘤模型中，采用分开的免疫方法可显示出具有不同DC的优势和优势Ags，促进了对所有Ags的CTL反应，并防止了肿瘤逃逸。这些发现对未来组合癌症免疫疗法的设计有影响。DC上的B7-H1表达可能有助于维持对多种肿瘤Ag的CTL反应的多样性。有趣的是，在鼠类肿瘤模型中，采用分开的免疫方法可显示出具有不同DC的优势和优势Ags，促进了对所有Ags的CTL反应，并防止了肿瘤逃逸。这些发现对未来组合癌症免疫疗法的设计有影响。DC上的B7-H1表达可能有助于维持对多种肿瘤Ag的CTL反应的多样性。有趣的是，在鼠类肿瘤模型中，采用分开的免疫方法可显示出具有不同DC的优势和优势Ags，促进了对所有Ags的CTL反应，并防止了肿瘤逃逸。这些发现对未来组合癌症免疫疗法的设计有影响。