Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer.
Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer.
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DOI：
10.3390/ijms23158479
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发表时间：
2022-07-30
影响因子：
5.6
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中科院分区：
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三阴性乳腺癌（TNBC）是一种免疫异质性疾病，缺乏临床可操作的靶点，并且比其他类型的乳腺癌更有可能进展为转移性疾病。肿瘤消融已被用于增加对检查点抑制剂的应答率，这对于TNBC患者来说仍然很低。我们假设，如果免疫抑制（即，肿瘤酸中毒）的症状得到缓解。将肿瘤用碳酸氢钠（200 mM p.o.）以减少肿瘤酸中毒和低剂量环磷酰胺（100-200 mg/kg i. p.）耗尽调节性T细胞，如先前研究中独立显示的那样。然后使用一种新型的可注射消融剂使肿瘤坏死，释放肿瘤抗原，并引发可产生远位效应的免疫事件。碳酸氢盐、环磷酰胺和消融的这种组合（称为“BiCyclA”）在三种TNBC同基因模型中进行了测试：E0771（C57 BL/6）、67 NR（BALB/c）和4 T1-Luc（BALB/c）。在E0771和67 NR中，BiCyclA治疗显著减少肿瘤生长，并在治疗后50天分别治愈5/7和6/10只小鼠。在手术和检查点抑制剂失败的转移性4 T1-Luc肿瘤中，BiCyclA治愈了5/10只小鼠的原发性肿瘤和肺转移。值得注意的是，发现CD 4+和CD 8 + T细胞对于抗转移反应至关重要，并且治愈的小鼠能够抵抗肿瘤再攻击，这表明免疫记忆的产生。通过消融降低肿瘤酸度和调节性T细胞是一种简单而有效的局部和全身肿瘤控制疗法，具有广泛的适用性，因为它不受昂贵供应的限制。
Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100–200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called “BiCyclA”, was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies.
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3.7
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