Georgopoulos Apostolos P, James Lisa M
The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA.
Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
BJC Rep. 2023 Oct 23;1(1):17. doi: 10.1038/s44276-023-00017-7.
Natural elimination of cancer cells is mediated by human leucocyte antigen (HLA) Class I and II molecules [1] that bind to tumour protein fragments, move to the tumour cell surface and engage CD8+ lymphocytes for killing the tumour cell (HLA Class I) and CD4+ lymphocytes for antibody production against the tumour cell (HLA Class II). HLA Class I molecules are present in all nucleated cells, whereas Class II molecules are present only in antigen presenting cells, such as macrophages. These defence mechanisms are suppressed by tumour cells; this tumour-induced immunosuppression is partly reversed by immune checkpoint inhibitors (ICI), thus allowing the HLA-based tumour elimination to be active again; indeed, the success of ICI therapy partly depends on the HLA makeup of the recipient [2, 3]. Here, we propose a novel cancer immunotherapy consisting of administering the mRNA blueprints for the synthesis of specific HLA Class I molecules with high binding affinity and high immunogenicity to a tumour's neoantigens. This should maximise the effectiveness of HLA-mediated tumour elimination.
癌细胞的自然清除是由人类白细胞抗原（HLA）I类和II类分子介导的[1]，这些分子与肿瘤蛋白片段结合，转移到肿瘤细胞表面，并与CD8 +淋巴细胞结合以杀死肿瘤细胞（HLA I类），与CD4 +淋巴细胞结合以产生针对肿瘤细胞的抗体（HLA II类）。HLA I类分子存在于所有有核细胞中，而II类分子仅存在于抗原呈递细胞中，如巨噬细胞。这些防御机制被肿瘤细胞抑制；这种肿瘤诱导的免疫抑制被免疫检查点抑制剂（ICI）部分逆转，从而使基于HLA的肿瘤清除再次活跃；事实上，ICI治疗的成功部分取决于接受者的HLA组成[2,3]。在此，我们提出一种新型癌症免疫疗法，即给予用于合成对肿瘤新抗原具有高结合亲和力和高免疫原性的特定HLA I类分子的mRNA蓝图。这应该能最大限度地提高HLA介导的肿瘤清除的有效性。
