Rejection of immunogenic tumor clones is limited by clonal fraction.
Rejection of immunogenic tumor clones is limited by clonal fraction.
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免疫原性肿瘤克隆的排斥受到克隆分数的限制。
DOI：
10.7554/elife.41090
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发表时间：
2018-11-30
期刊：
影响因子：
7.7
通讯作者：
Scheinberg DA
中科院分区：
文献类型：
--
作者：
Gejman RS;Chang AY;Jones HF;DiKun K;Hakimi AA;Schietinger A;Scheinberg DA
肿瘤通常与识别癌细胞在主要组织相容性复合体I（MHC-I）上呈递的体细胞突变肽的T细胞共存。然而，目前还不清楚为什么免疫系统不能消除免疫可识别的肿瘤之前，他们表现为坦率的疾病。为了了解新生肿瘤中MHC-I肽免疫原性的决定因素，我们通过使用新的“PresentER”抗原呈递平台测试了数千种MHC-I配体在免疫活性小鼠中引起肿瘤亚克隆排斥的能力。令人惊讶的是，我们表明，免疫原性肿瘤抗原不会导致免疫介导的细胞排斥时，每个抗原的细胞的分数（克隆分数）低。此外，导致免疫原性肿瘤亚克隆排斥所需的克隆分数取决于抗原。这些数据表明，肿瘤新抗原异质性对癌细胞的免疫消除具有未被充分认识的影响，并对免疫治疗剂如癌症疫苗的设计具有影响。T细胞是免疫系统的专门试剂，可以检测和攻击肿瘤。他们通过识别病变细胞表面的小块蛋白质或抗原来发现目标。特别是，它们可以识别癌细胞经常显示的新的和异常的抗原。然而，癌变并开始显示可疑抗原的细胞可以设法逃离T细胞并生长成完整的肿瘤。为什么免疫系统不能在这些早期癌症失控之前识别并杀死它们？一种可能性是T细胞不能识别癌细胞携带的某些抗原。为了验证这一点，研究人员进行了实验，他们给小鼠注射了展示单一新抗原的癌细胞。如果动物发生肿瘤，那么这种抗原不会引发免疫反应。然而，这种方法缓慢且费力，因为当时只能测试一种抗原。相反，Gejman，Chang等人开发了一种新技术PresentER，其中啮齿动物被注射了数百万个癌细胞的混合物，每个癌细胞都显示出不同的抗原。通过这种方式，可以一次性研究数千种新抗原。肿瘤在被切除和分析之前会生长几周，以观察哪些细胞存活，哪些细胞被免疫系统杀死。出乎意料的是，抗原的性质并没有造成很大的差异。相反，如果带有新抗原的癌细胞很罕见，并且只占肿瘤中所有不同癌细胞的一小部分，那么它们可能无法被检测到。然而，当癌细胞是癌性肿块的主要成分时，免疫系统会消除完全相同的癌细胞。未来的研究现在必须探索罕见的癌细胞如何隐藏在其他细胞中，并保持身体不可见。有了这些知识，就有可能通过促使免疫系统更早地针对这些新出现的威胁来改善癌症治疗。
Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new ‘PresentER’ antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen (‘clonal fraction’) is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines. T cells are specialized agents of the immune system that can detect and attack tumors. They spot their target by identifying small pieces of proteins – or antigens – at the surface of diseased cells. In particular, they can recognize the new and abnormal antigens that a cancer cell often displays. Yet, cells that become cancerous and start displaying suspicious antigens can manage to escape T cells and grow into full tumors. Why does the immune system not recognize and kill these early cancers before they get out of control? One possibility is that T cells do not identify certain antigens carried by cancer cells. To test this, researchers have conducted experiments where they inject a mouse with cancer cells that display a single new antigen. If the animal develops a tumor, then this antigen does not trigger an immune response. However, this method is slow and laborious, because only one antigen can be tested at the time. Instead, Gejman, Chang et al. developed a new technique, PresentER, where a rodent gets injected with a mix of millions cancer cells that each displays a different antigen. This way, many thousands of new antigens can be studied in one go. The tumors are left to grow for several weeks before they are removed and analyzed to see which cells survived and which have been killed by the immune system. Unexpectedly, the nature of the antigen did not make a big difference. Instead, cancer cells with new antigens could go undetected if they were rare and made up only a small proportion of all the different cancer cells in a tumor. However, the immune system would eliminate the exact same cancer cells when they were the major component of a cancerous lump. Future research now has to explore exactly how rare cancer cells can hide amongst other cells, and remain invisible to the body. Armed with this knowledge, it might be possible to improve cancer therapy by prompting the immune system to target these emerging threats earlier.