By overexpression of specific transcription factors, in vivo cell reprogramming has potential for treating ‘cold’ tumors that are often resistant to immune checkpoint blockade (ICB). A study in Science now shows that tumor cells in vivo can be reprogrammed to resemble type 1 conventional dendritic cells (cDC1s) and in so doing overcome these poorly immunogenic tumor conditions by boosting the presentation of tumor antigens. The researchers had previously found that the combination of the transcription factors PU.1, IRF8 and BATF3 (PIB) in vitro was sufficient to differentiate cancer cells in this manner, but they now demonstrate that this can be done in vivo using a gene-therapy approach in mouse melanoma models (and human spheroids). They injected replication-deficient viral vectors carrying PIB into the tumors and saw conversion of melanoma cells into cDC1-like cells with professional antigen-presenting capacity to activate anti-tumor T cell responses and limit tumor growth. In addition, the treatment resulted in immunological memory as there was durable protection against tumor rechallenge and against lung metastases. This method could avoid the costs and difficulties associated with ex vivo cell culture immunotherapies and boost or even replace ICB in resistant tumors.

Original reference: Science https://doi.org/10.1126/science.adn9083 (2024)

通过特定转录因子的过度表达，体内细胞重编程具有治疗通常对免疫检查点阻断（ICB）具有抵抗力的“冷”肿瘤的潜力。 《科学》杂志上的一项研究现在表明，体内肿瘤细胞可以被重新编程为类似于 1 型传统树突状细胞 (cDC1)，从而通过增强肿瘤抗原的呈递来克服这些免疫原性较差的肿瘤状况。研究人员此前发现，转录因子 PU.1、IRF8 和 BATF3 (PIB) 在体外的组合足以以这种方式分化癌细胞，但他们现在证明，这可以使用基因疗法在体内完成小鼠黑色素瘤模型（和人类球体）中的方法。他们将携带 PIB 的复制缺陷型病毒载体注射到肿瘤中，发现黑色素瘤细胞转化为具有专业抗原呈递能力的 cDC1 样细胞，可激活抗肿瘤 T 细胞反应并限制肿瘤生长。此外，该治疗还产生了免疫记忆，因为对肿瘤再攻击和肺转移有持久的保护作用。这种方法可以避免与离体细胞培养免疫疗法相关的成本和困难，并增强甚至取代耐药肿瘤中的 ICB。

Original reference: Science https://doi.org/10.1126/science.adn9083 (2024)