Loss of target antigens in tumor cells has become one of the major hurdles limiting the efficacy of adoptive cell therapy (ACT)-based immunotherapies. The optimal approach to overcome this challenge includes broadening the immune response from the initially targeted tumor-associated antigen (TAA) to other TAAs expressed in the tumor. To induce a more broadly targeted antitumor response, we utilized our previously developed Re-energized ACT (ReACT), which capitalizes on the synergistic effect of pathogen-based immunotherapy and ACT. In this study, we showed that ReACT induced a sufficient endogenous CD8+ T-cell response beyond the initial target to prevent the outgrowth of antigen loss variants in a B16-F10 melanoma model. Sequentially, selective depletion experiments revealed that Batf3-driven cDC1s were essential for the activation of endogenous tumor-specific CD8+ T cells. In ReACT-treated mice that eradicated tumors, we observed that endogenous CD8+ T cells differentiated into memory cells and facilitated the rejection of local and distal tumor rechallenge. By targeting one TAA with ReACT, we provided broader TAA coverage to counter antigen escape and generate a durable memory response against local relapse and metastasis.See related Spotlight on p. 2.

中文翻译：

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病原体增强的过继细胞转移疗法通过抗原扩散诱导内源性抗肿瘤免疫。

肿瘤细胞中靶抗原的丢失已成为限制基于过继细胞疗法（ACT）的免疫疗法疗效的主要障碍之一。克服这一挑战的最佳方法包括将免疫反应从最初靶向的肿瘤相关抗原 (TAA) 扩大到肿瘤中表达的其他 TAA。为了诱导更广泛的靶向抗肿瘤反应，我们利用了之前开发的 Re-energized ACT (ReACT)，它利用了基于病原体的免疫疗法和 ACT 的协同效应。在这项研究中，我们表明 ReACT 诱导了超出初始目标的足够的内源性 CD8+ T 细胞反应，以防止 B16-F10 黑色素瘤模型中抗原丢失变异的生长。随后，选择性耗竭实验表明，Batf3 驱动的 cDC1 对于内源性肿瘤特异性 CD8+ T 细胞的激活至关重要。在根除肿瘤的 ReACT 治疗小鼠中，我们观察到内源性 CD8+ T 细胞分化为记忆细胞，并促进局部和远端肿瘤再攻击的排斥。通过使用 ReACT 靶向一个 TAA，我们提供了更广泛的 TAA 覆盖范围，以对抗抗原逃逸，并针对局部复发和转移产生持久的记忆反应。请参阅第 11 页上的相关聚焦。2.