Over the last two decades, the diagnosis and treatment of breast cancer patients have considerably improved. However, brain metastases remain a major clinical challenge and a leading cause of mortality. Thus, a better understanding of the pathways involved in the metastatic cascade is essential. To this end, we have investigated the reciprocal effects of astrocytes and breast cancer cells, employing traditional 2-dimensional cell culture and our unique 3-dimensional multicellular tumoroid models. Our findings revealed that astrocytes enhance the proliferation, migration, and invasion of breast cancer cells, suggesting a supportive role for astrocytes in breast cancer outgrowth to the brain. Elucidating the key players in astrocyte-breast cancer cells crosstalk, we found that CCL2 is highly expressed in breast cancer brain metastases tissue sections from both patients and mice. Our in vitro and in vivo models further confirmed that CCL2 has a functional role in brain metastasis. Given their aggressive nature, we sought additional immune checkpoints for rationale combination therapy. Among the promising candidates were the adhesion molecule P-selectin, which we have recently shown to play a key role in the crosstalk with microglia cells, and the co-inhibitory receptor PD-1, the main target of currently approved immunotherapies. Finally, combining CCL2 inhibition with immunomodulators targeting either PD-1/PD-L1 or P-selectin/P-Selectin Ligand-1 axes in our human 3-dimensional tumoroid models and in vivo presented more favorable outcomes than each monotherapy. Taken together, we propose that CCL2-CCR2/CCR4 is a key pathway promoting breast cancer brain metastases and a promising target for an immunotherapeutic combination approach.

中文翻译：

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CCL2 阻断联合 PD-1/P-选择素免疫调节剂阻碍乳腺癌脑转移


在过去的二十年里，乳腺癌患者的诊断和治疗有了很大的改善。然而，脑转移仍然是一个主要的临床挑战和导致死亡的主要原因。因此，更好地了解转移级联反应中涉及的途径至关重要。为此，我们研究了星形胶质细胞和乳腺癌细胞的相互效应，采用传统的 2 维细胞培养和我们独特的 3 维多细胞肿瘤模型。我们的研究结果表明，星形胶质细胞增强乳腺癌细胞的增殖、迁移和侵袭，表明星形胶质细胞在乳腺癌向大脑生长中的支持作用。阐明星形胶质细胞-乳腺癌细胞串扰的关键参与者，我们发现 CCL2 在患者和小鼠的乳腺癌脑转移组织切片中均高度表达。我们的体外和体内模型进一步证实 CCL2 在脑转移中具有功能作用。鉴于它们的侵袭性，我们寻求额外的免疫检查点进行 rationale 联合治疗。有前途的候选者包括粘附分子 P-选择素，我们最近证明它在与小胶质细胞的串扰中起关键作用，以及共抑制受体 PD-1，这是目前批准的免疫疗法的主要靶点。最后，在我们的人类 3 维肿瘤样模型和体内将 CCL2 抑制与靶向 PD-1/PD-L1 或 P-选择素/P-选择素配体-1 轴的免疫调节剂相结合，比每种单一疗法都显示出更有利的结果。综上所述，我们提出 CCL2-CCR2/CCR4 是促进乳腺癌脑转移的关键通路，也是免疫治疗联合方法的有前途的靶点。