Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan.
Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
Nat Rev Clin Oncol. 2024 May;21(5):337-353. doi: 10.1038/s41571-024-00870-6. Epub 2024 Feb 29.
Accumulating evidence indicates that aberrant signalling stemming from genetic abnormalities in cancer cells has a fundamental role in their evasion of antitumour immunity. Immune escape mechanisms include enhanced expression of immunosuppressive molecules, such as immune-checkpoint proteins, and the accumulation of immunosuppressive cells, including regulatory T (T) cells, in the tumour microenvironment. Therefore, T cells are key targets for cancer immunotherapy. Given that therapies targeting molecules predominantly expressed by T cells, such as CD25 or GITR, have thus far had limited antitumour efficacy, elucidating how certain characteristics of cancer, particularly genetic abnormalities, influence T cells is necessary to develop novel immunotherapeutic strategies. Hence, T cell-targeted strategies based on the particular characteristics of cancer in each patient, such as the combination of immune-checkpoint inhibitors with molecularly targeted agents that disrupt the immunosuppressive networks mediating T cell recruitment and/or activation, could become a new paradigm of cancer therapy. In this Review, we discuss new insights on the mechanisms by which cancers generate immunosuppressive networks that attenuate antitumour immunity and how these networks confer resistance to cancer immunotherapy, with a focus on T cells. These insights lead us to propose the concept of 'immuno-genomic precision medicine' based on specific characteristics of cancer, especially genetic profiles, that correlate with particular mechanisms of tumour immune escape and might, therefore, inform the optimal choice of immunotherapy for individual patients.
越来越多的证据表明，癌细胞中遗传异常导致的异常信号在其逃避抗肿瘤免疫中起着根本作用。免疫逃逸机制包括免疫抑制分子（如免疫检查点蛋白）的表达增强，以及肿瘤微环境中免疫抑制细胞（如调节性 T [T] 细胞）的积累。因此，T 细胞是癌症免疫治疗的关键靶点。鉴于针对 T 细胞主要表达的分子（如 CD25 或 GITR）的治疗方法迄今为止抗肿瘤疗效有限，阐明某些癌症特征（尤其是遗传异常）如何影响 T 细胞对于开发新的免疫治疗策略是必要的。因此，基于每位患者癌症的特定特征（例如，将免疫检查点抑制剂与分子靶向药物联合使用，破坏介导 T 细胞募集和/或激活的免疫抑制网络）的 T 细胞靶向策略可能成为癌症治疗的新模式。在这篇综述中，我们讨论了癌症产生抑制抗肿瘤免疫的免疫抑制网络的机制的新见解，以及这些网络如何赋予癌症免疫治疗的耐药性，重点是 T 细胞。这些见解使我们提出了基于癌症的特定特征（尤其是遗传谱）的“免疫基因组精准医学”概念，这些特征与肿瘤免疫逃逸的特定机制相关，因此可能为每位患者选择最佳的免疫治疗提供信息。
