Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, Virginia.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.
Cancer Immunol Res. 2021 Nov;9(11):1327-1341. doi: 10.1158/2326-6066.CIR-21-0111. Epub 2021 Aug 19.
Elevated immunity to cancer-expressed antigens can be detected in people with no history of cancer and may contribute to cancer prevention. We have previously reported that MHC-restricted phosphopeptides are cancer-expressed antigens and targets of immune recognition. However, the extent to which this immunity reflects prior or ongoing phosphopeptide exposures was not investigated. In this study, we found that preexisting immune memory to cancer-expressed phosphopeptides was evident in most healthy donors, but the breadth among donors was highly variable. Although three phosphopeptides were recognized by most donors, suggesting exposures to common microbial/infectious agents, most of the 205 tested phosphopeptides were not recognized by peripheral blood mononuclear cells (PBMC) from any donor and the remainder were recognized by only 1 to 3 donors. In longitudinal analyses of 2 donors, effector immune response profiles suggested active reexposures to a subset of phosphopeptides. These findings suggest that the immunogens generating most phosphopeptide-specific immune memory are rare infectious agents or incipient cancer cells with distinct phosphoproteome dysregulations, and that repetitive immunogenic exposures occur in individual donors. Phosphopeptide-specific immunity in PBMCs and tumor-infiltrating lymphocytes from ovarian cancer patients was limited, regardless of whether the phosphopeptide was expressed on the tumor. However, 4 of 10 patients responded to 1 to 2 immunodominant phosphopeptides, and 1 showed an elevated effector response to a tumor-expressed phosphopeptide. As the tumors from these patients displayed many phosphopeptides, these data are consistent with lack of prior exposure or impaired ability to respond to some phosphopeptides and suggest that enhancing phosphopeptide-specific T-cell responses could be a useful approach to improve tumor immunotherapy.
在没有癌症病史的人群中可以检测到针对癌症表达抗原的高免疫性，这可能有助于癌症预防。我们之前曾报道过 MHC 限制性磷酸肽是癌症表达的抗原和免疫识别的靶标。然而，这种免疫反应在多大程度上反映了先前或正在进行的磷酸肽暴露尚未得到研究。在这项研究中，我们发现大多数健康供体中存在针对癌症表达磷酸肽的预先存在的免疫记忆，但供体之间的广度差异很大。虽然大多数供体识别到三种磷酸肽，提示它们暴露于常见的微生物/感染性抗原，但在测试的 205 种磷酸肽中，大多数都没有被任何供体的外周血单核细胞 (PBMC) 识别，其余的只被 1 到 3 个供体识别。对 2 个供体的纵向分析表明，效应免疫反应谱提示对一组磷酸肽进行了主动再暴露。这些发现表明，产生大多数磷酸肽特异性免疫记忆的免疫原是罕见的感染性抗原或具有独特磷酸蛋白质组失调的早期癌细胞，并且个体供体中会发生重复的免疫原性暴露。卵巢癌患者的 PBMC 和肿瘤浸润淋巴细胞中的磷酸肽特异性免疫受到限制，无论该磷酸肽是否在肿瘤上表达。然而，在 10 名患者中的 4 名对 1 到 2 种免疫显性磷酸肽有反应，并且 1 名患者对肿瘤表达的磷酸肽表现出升高的效应器反应。由于这些患者的肿瘤显示出许多磷酸肽，这些数据与缺乏先前暴露或对某些磷酸肽的反应能力受损一致，并表明增强磷酸肽特异性 T 细胞反应可能是改善肿瘤免疫治疗的一种有用方法。
