Endogenous antitumor effector T-cell responses and immune-suppressive regulatory T cells (Treg) critically influence the prognosis of patients with cancer, yet many of the mechanisms of how this occurs remain unresolved. On the basis of an analysis of the function, antigen specificity, and distribution of tumor antigen-reactive T cells and Tregs in patients with breast cancer and transgenic mouse tumor models, we showed that tumor-specific Tregs were selectively activated in the bone marrow (BM) and egressed into the peripheral blood. The BM was constantly depleted of tumor-specific Tregs and was instead a site of increased induction and activity of tumor-reactive effector/memory T cells. Treg egress from the BM was associated with activation-induced expression of peripheral homing receptors such as CCR2. Because breast cancer tissues express the CCR2 ligand CCL2, the activation and egress of tumor antigen-specific Tregs in the BM resulted in the accumulation of Tregs in breast tumor tissue. Such immune compartmentalization and redistribution of T-cell subpopulations between the BM and peripheral tissues were achieved by vaccination with adenoviral vector-encoded TRP-2 tumor antigen in a RET transgenic mouse model of spontaneous malignant melanoma. Thus, the BM simultaneously represented a source of tumor-infiltrating Tregs and a site for the induction of endogenous tumor-specific effector T-cell responses, suggesting that both antitumor immunity and local immune suppression are orchestrated in the BM.

中文翻译：

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来自乳腺癌的骨髓抗肿瘤免疫力的肿瘤特异性调节性T细胞。

内源性抗肿瘤效应T细胞反应和免疫抑制调节性T细胞（Treg）会严重影响癌症患者的预后，但是如何发生这种现象的许多机制仍未得到解决。在对乳腺癌和转基因小鼠肿瘤模型患者的功能，抗原特异性以及肿瘤抗原反应性T细胞和Treg的分布进行分析的基础上，我们表明肿瘤特异性Treg在骨髓中被选择性激活（ BM）并进入外周血。BM不断耗尽肿瘤特异性Treg，而成为肿瘤反应性效应子/记忆T细胞诱导和活性增加的部位。Treg从BM流出与激活诱导的外周血归巢受体如CCR2的表达有关。因为乳腺癌组织表达CCR2配体CCL2，所以BM中肿瘤抗原特异性Treg的激活和流出导致Treg在乳腺癌组织中的积累。通过在自发性恶性黑素瘤的RET转基因小鼠模型中接种腺病毒载体编码的TRP-2肿瘤抗原，可以实现BM与周围组织之间的这种免疫间隔和T细胞亚群的重新分布。因此，BM同时代表肿瘤浸润性Treg的来源和诱导内源性肿瘤特异性效应T细胞反应的位点，表明BM中精心策划了抗肿瘤免疫力和局部免疫抑制作用。通过在自发性恶性黑色素瘤的RET转基因小鼠模型中接种腺病毒载体编码的TRP-2肿瘤抗原，可以实现BM与周围组织之间的这种免疫间隔和T细胞亚群的重新分布。因此，BM同时代表肿瘤浸润性Treg的来源和诱导内源性肿瘤特异性效应T细胞反应的位点，表明BM中精心策划了抗肿瘤免疫力和局部免疫抑制作用。通过在自发性恶性黑色素瘤的RET转基因小鼠模型中接种腺病毒载体编码的TRP-2肿瘤抗原，可以实现BM与周围组织之间的这种免疫间隔和T细胞亚群的重新分布。因此，BM同时代表肿瘤浸润性Treg的来源和诱导内源性肿瘤特异性效应T细胞反应的位点，表明BM中精心策划了抗肿瘤免疫力和局部免疫抑制作用。