Neoadjuvant immunotherapy, given before surgical resection, is a promising approach to develop systemic antitumor immunity for the treatment of high-risk resectable disease. Here, using syngeneic and orthotopic mouse models of triple-negative breast cancer, we have tested the hypothesis that generation of tumor-specific T-cell responses by induction and activation of tumor-residing Batf3-dependent conventional type 1 dendritic cells (cDC1) before resection improves control of distant metastatic disease and survival. Mice bearing highly metastatic orthotopic tumors were treated with a combinatorial in situ immunomodulation (ISIM) regimen comprised of intratumoral administration of Flt3L, local radiotherapy, and in situ TLR3/CD40 stimulations, followed by surgical resection. Neoadjuvant ISIM (neo-ISIM) generated tumor-specific CD8+ T cells that infiltrated into distant nonirradiated metastatic sites, which delayed the progression of lung metastases and improved survival after the resection of primary tumors. The efficacy of neo-ISIM was dependent on de novo adaptive T-cell immunity elicited by Batf3-dependent dendritic cells and was enhanced by increasing dose and fractionation of radiotherapy, and early surgical resection after the completion of neo-ISIM. Importantly, neo-ISIM synergized with programmed cell death protein-1 ligand-1 (PD-L1) blockade to improve control of distant metastases and prolong survival, while removal of tumor-draining lymph nodes abrogated the antimetastatic efficacy of neo-ISIM. Our findings illustrate the therapeutic potential of neoadjuvant multimodal intralesional therapy for the treatment of resectable tumors with high risk of relapse. Significance: Neoadjuvant induction and activation of cDC1s in primary tumors enhances systemic antitumor immunity, suppresses metastatic progression, improves survival, and synergizes with anti–PD-L1 therapy.

中文翻译：

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新辅助原位免疫调节增强针对高度转移性肿瘤的全身抗肿瘤免疫

在手术切除前给予新辅助免疫治疗，是一种有前途的方法，可以发展系统性抗肿瘤免疫，以治疗高危可切除疾病。在这里，使用三阴性乳腺癌的同基因和原位小鼠模型，我们已经测试了通过诱导和激活肿瘤内的 Batf3 依赖性常规 1 型树突状细胞 (cDC1) 来产生肿瘤特异性 T 细胞反应的假设。切除改善了对远处转移性疾病的控制和生存率。携带高转移性原位肿瘤的小鼠接受了一种组合原位免疫调节 (ISIM) 方案，该方案包括 Flt3L 的瘤内给药、局部放疗和原位 TLR3/CD40 刺激，然后进行手术切除。新辅助 ISIM (neo-ISIM) 产生了肿瘤特异性 CD8+ T 细胞，这些细胞浸润到远处未受照射的转移部位，从而延缓了肺转移的进展并提高了原发性肿瘤切除后的生存率。neo-ISIM 的疗效依赖于 Batf3 依赖性树突状细胞引发的从头适应性 T 细胞免疫，并通过增加放射治疗的剂量和分割以及 Neo-ISIM 完成后的早期手术切除来增强。重要的是，neo-ISIM 与程序性细胞死亡蛋白-1 配体-1 (PD-L1) 阻断协同作用以改善对远处转移的控制并延长生存期，而切除肿瘤引流淋巴结则消除了 neo-ISIM 的抗转移功效。我们的研究结果说明了新辅助多模式病灶内治疗在治疗具有高复发风险的可切除肿瘤中的治疗潜力。意义：新辅助诱导和激活原发性肿瘤中的 cDC1 可增强全身抗肿瘤免疫，抑制转移进展，提高生存率，并与抗 PD-L1 治疗协同作用。