Dendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response.
Dendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response.
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DOI：
10.1158/1078-0432.ccr-19-1321
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发表时间：
2020-08-01
期刊：
影响因子：
--
通讯作者：
Luke JJ
中科院分区：
文献类型：
--
作者：
Garris CS;Luke JJ
实体瘤中最成功的癌症免疫疗法--免疫检查点阻断--的发展集中在调节T细胞活化的因子上。直到最近，该领域一直保持着以T细胞为中心的免疫治疗观点，而不考虑先天免疫，特别是骨髓细胞的影响。树突状细胞（DC）是T细胞的主要伙伴，是启动适应性免疫应答所必需的。新出现的证据支持DC在肿瘤中发挥更广泛的作用，包括在T细胞应答期间维持和支持效应子功能。这种关系通过活化的DC与免疫检查点阻断应答的关联以及应答肿瘤的转录分析证明存在I型干扰素转录物和DC相关趋化因子来证明。与非T细胞炎症肿瘤相比，T细胞炎症肿瘤优先响应免疫疗法，并且该模型表明肿瘤微环境免疫的潜在可修改谱。虽然宿主和宿主因素可能限制T细胞发炎表型，但肿瘤细胞内在因素作为治疗靶点越来越突出。例如，肿瘤WNT/β-连环蛋白信号传导抑制趋化因子梯度的产生并阻断DC向肿瘤的募集。相反，先天免疫核酸传感机制，通常在病原体反应过程中起作用，可能会增强DC积累，使肿瘤更容易受到癌症免疫治疗。阐明DCs在肿瘤中浸润和激活的机制可能为治疗干预提供新的机会。从概念上讲，这将促进非T细胞炎症转化为T细胞炎症状态，或克服T细胞炎症肿瘤中的继发性耐药机制，扩大受益于癌症免疫治疗的患者比例。
The development of the most successful cancer immunotherapies in solid tumors, immune-checkpoint blockade, has focused on factors regulating T cell activation. Until recently, the field has maintained a predominately T-cell centric view of immunotherapy, leaving aside the impact of innate immunity and especially myeloid cells. Dendritic cells (DC) are dominant partners of T cells, necessary for initiation of adaptive immune responses. Emerging evidence supports a broader role for DCs in tumors including the maintenance and support of effector functions during T cell responses. This relationship is evidenced by the association of activated DCs with immune-checkpoint blockade responses and transcriptional analysis of responding tumors demonstrating the presence of type I interferon transcripts and DC relevant chemokines. T cell-inflamed tumors preferentially respond to immunotherapies compared to non-T cell inflamed tumors and this model suggests a potentially modifiable spectrum of tumor microenvironmental immunity. While host and commensal factors may limit the T cell-inflamed phenotype, tumor cell intrinsic factors are gaining prominence as therapeutic targets. For example, tumor WNT/β-catenin signaling inhibits production of chemokine gradients and blocking DC recruitment to tumors. Conversely, mechanisms of innate immune nucleic acid sensing, normally operative during pathogen response, may enhance DC accumulation and make tumors more susceptible to cancer immunotherapy. Elucidating mechanisms whereby DCs infiltrate and become activated within tumors may provide new opportunities for therapeutic intervention. Conceptually, this would facilitate conversion of non-T cell-inflamed to T cell-inflamed states or overcome secondary resistance mechanisms in T cell-inflamed tumors, expanding the proportion of patients who benefit from cancer immunotherapy.