Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression.
Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression.
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DOI：
10.7554/elife.85263
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发表时间：
2023-08-07
期刊：
影响因子：
7.7
通讯作者：
Spranger S
中科院分区：
文献类型：
--
作者：
Nguyen KB;Roerden M;Copeland CJ;Backlund CM;Klop-Packel NG;Remba T;Kim B;Singh NK;Birnbaum ME;Irvine DJ;Spranger S
癌症免疫疗法，特别是检查点阻断免疫疗法（CBT），可以诱导控制癌症生长，一部分患者经历持久的反应。然而，目前大多数患者对CBT没有反应，并且耐药的分子决定因素尚未完全阐明。越来越多的临床证据表明，新抗原（NeoAg）的克隆状态影响抗肿瘤T细胞应答。高肿瘤内异质性（ITH），其中大多数NeoAg亚克隆表达，与CBT临床反应差和肿瘤反应性T细胞浸润差相关。然而，ITH钝化肿瘤反应性T细胞的机制尚不清楚。我们开发了一种可移植的鼠肺癌模型，以表征针对一组定义的克隆或亚克隆表达的NeoAg的免疫应答，以分别模拟低或高ITH。在这里，我们表明，克隆表达的弱免疫原性NeoAg与相对较强的NeoAg增加了免疫原性肿瘤低，但不是高ITH。从机制上讲，我们确定克隆NeoAg表达允许交叉呈递树突状细胞获得并呈递两种NeoAg。树突状细胞的双重NeoAg呈递与更成熟的DC表型和更高的刺激能力相关。这些数据表明，克隆NeoAg表达可以诱导更有效的抗肿瘤反应，由于更多的刺激性树突状细胞：T细胞的相互作用。靶向亚克隆表达的NeoAg的治疗性疫苗接种可用于增强抗肿瘤T细胞应答。
Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been fully elucidated. Mounting clinical evidence suggests that the clonal status of neoantigens (NeoAg) impacts the anti-tumor T cell response. High intratumor heterogeneity (ITH), where the majority of NeoAgs are expressed subclonally, is correlated with poor clinical response to CBT and poor infiltration with tumor-reactive T cells. However, the mechanism by which ITH blunts tumor-reactive T cells is unclear. We developed a transplantable murine lung cancer model to characterize the immune response against a defined set of NeoAgs expressed either clonally or subclonally to model low or high ITH, respectively. Here we show that clonal expression of a weakly immunogenic NeoAg with a relatively strong NeoAg increased the immunogenicity of tumors with low but not high ITH. Mechanistically we determined that clonal NeoAg expression allowed cross-presenting dendritic cells to acquire and present both NeoAgs. Dual NeoAg presentation by dendritic cells was associated with a more mature DC phenotype and a higher stimulatory capacity. These data suggest that clonal NeoAg expression can induce more potent anti-tumor responses due to more stimulatory dendritic cell:T cell interactions. Therapeutic vaccination targeting subclonally expressed NeoAgs could be used to boost anti-tumor T cell responses.