CD103⁺ dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c⁺ monocytic precursors. These Ly6c⁺CD103⁺ cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c⁺CD103⁺ phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6c⁺CD103⁺ population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6c⁺CD103⁺ cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6c⁺CD103⁺ monocytic cells represents a potent and previously unrecognized target for immunotherapy.

CD103 ⁺树突状细胞对于肿瘤抗原的交叉呈递至关重要。在这里，我们已经表明，在免疫治疗过程中，通过Ly6c ⁺单核细胞前体的直接分化，大量表达CD103的细胞在鼠肿瘤中出现。这些Ly6c ⁺ CD103 ⁺细胞可能源自骨髓单核祖细胞（cMoP）或源自髓样抑制细胞（MDSC）群体中的外周细胞。分化是由炎症诱导的转录因子p53激活控制的，转录因子p53激活了Batf3的上调和Ly6c ⁺ CD103 ⁺表型的获得。在髓样细胞中靶向删除p53的小鼠选择性丢失了Ly6c⁺ CD103 ⁺人口，无法对多种形式的免疫疗法和免疫原性化学疗法作出反应。相反，在免疫治疗期间，使用p53激动剂药物增加p53表达会导致肿瘤中Ly6c ⁺ CD103 ⁺细胞的持续增加，从而显着增强了疗效和反应持续时间。因此，p53驱动的Ly6c ⁺ CD103 ⁺单核细胞分化代表了一种有效且以前无法识别的免疫疗法靶标。