Chemical induction of splice-neoantigens attenuates tumor growth in a preclinical model of colorectal cancer
Chemical induction of splice-neoantigens attenuates tumor growth in a preclinical model of colorectal cancer
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DOI：
10.1126/scitranslmed.abn6056
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发表时间：
2022-11
影响因子：
17.1
通讯作者：
Shingo Matsushima;M. Ajiro;K. Iida;K. Chamoto;T. Honjo;M. Hagiwara
中科院分区：
文献类型：
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作者：
Shingo Matsushima;M. Ajiro;K. Iida;K. Chamoto;T. Honjo;M. Hagiwara
新抗原的产生是癌症免疫治疗的决定因素。然而，用于癌症治疗的新抗原丰度的扩展在技术上具有挑战性。在这里，我们报告说，合成化合物RECTAS可以诱导产生剪接新抗原，可用于增强抗肿瘤免疫反应。RECTAS以CD 8 + T细胞和肿瘤主要组织相容性复合物I类依赖性方式抑制肿瘤生长，并增强免疫检查点阻断功效。随后的转录组分析和免疫原性验证鉴定了6种剪接新抗原候选物，其表达由RECTAS治疗诱导。除了在用RECTAS致敏后抑制体内肿瘤生长之外，所鉴定的新表位的疫苗接种引发了能够在体外杀死癌细胞的T细胞应答。总的来说，这些结果为进一步开发用于癌症免疫治疗的剪接变体诱导治疗提供了支持。描述用合成化合物RECTAS化学诱导富含丝氨酸/丝氨酸的剪接因子Ⅶ依赖性剪接新抗原，增强抗肿瘤免疫力。当新抗原以高丰度存在时，癌症免疫疗法最有效。然而，一些类型的癌症不具有高肿瘤突变负荷，因此不具有许多新抗原。在这里，Matsushima等人使用了另一种方法来产生新抗原。作者使用一种名为RECTAS的合成化合物在患有结直肠癌的小鼠中化学诱导剪接新抗原。RECTAS治疗以CD 8 + T细胞依赖性方式抑制肿瘤生长，并增强免疫检查点阻断。总之，这些结果表明，剪接调节剂值得进一步研究，作为癌症免疫治疗工具箱的一部分。厘米
Neoantigen production is a determinant of cancer immunotherapy. However, the expansion of neoantigen abundance for cancer therapeutics is technically challenging. Here, we report that the synthetic compound RECTAS can induce the production of splice-neoantigens that could be used to boost antitumor immune responses. RECTAS suppressed tumor growth in a CD8+ T cell– and tumor major histocompatibility complex class I–dependent manner and enhanced immune checkpoint blockade efficacy. Subsequent transcriptome analysis and validation for immunogenicity identified six splice-neoantigen candidates whose expression was induced by RECTAS treatment. Vaccination of the identified neoepitopes elicited T cell responses capable of killing cancer cells in vitro, in addition to suppression of tumor growth in vivo upon sensitization with RECTAS. Collectively, these results provide support for the further development of splice variant–inducing treatments for cancer immunotherapy. Description Chemical induction of serine/arginine-rich splicing factor‒dependent splice-neoantigens with a synthetic compound, RECTAS, boosts antitumor immunity. Splice and dice Cancer immunotherapy is most effective when neoantigens are present at high abundance. However, some types of cancer do not have a high tumor mutational burden and thus do not have many neoantigens. Here, Matsushima et al. used an alternative approach to generate neoantigens. The authors chemically induced splice-neoantigens in mice with colorectal cancer using a synthetic compound called RECTAS. RECTAS treatment suppressed tumor growth in a CD8+ T cell–dependent manner and also enhanced immune checkpoint blockade. Together, these results suggest that splicing modulators merit further investigation as part of the cancer immunotherapy toolbox.—CM.