常规树突状细胞(cDC)处于激活免疫系统以建立抗肿瘤免疫应答的最前沿。Flt3L是DC发育所需的细胞因子,其可以在治疗性施用时增加肿瘤中的DC丰度。然而,Flt3L对肿瘤微环境中不同cDC亚群表型的影响仍未确定。这里,使用多维单细胞分析,我们显示Flt3L治疗增加了原位E0771和TS/A乳腺癌和LLC肺癌模型中的所有cDC亚群,但这并没有导致任何模型中肿瘤生长的减少。有趣的是,CD81+migcDC1种群,在E0771肿瘤以及TS/A乳腺和LLC肺肿瘤中,Flt3L治疗可能诱导了cDC1。此CD81migcDC1子集的特征在于经典cDC1标记以及迁移cDC激活和调节标记的表达,并显示出Treg诱导潜力。为了将cDC表型转向T细胞刺激表型,将CD40激动剂疗法与Flt3L组合施用于E0771荷瘤小鼠。然而,而αCD40减少肿瘤生长,Flt3L未能改善对αCD40治疗的治疗反应。有趣的是,Flt3L+αCD40联合治疗增加了Treg促进CD81+migcDC1的丰度。尽管如此,而Treg消耗和αCD40治疗是协同的,在该组合中加入Flt3L没有产生任何额外的益处.总的来说,这些结果表明,通过Flt3L治疗仅增加肿瘤中的cDC不能改善抗肿瘤反应,因此可能不利于癌症的治疗,尽管仍可用于增加自体DC治疗的cDC数量。
Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response.
Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of
Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that
Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon
Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth,
Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy.