免疫逃逸：HLA loss了怎么破？

怪不得再怎么撸PD-1都没用，暂时还没系统性地梳理怎么破解

今早有大v在推上贴了一副比我年纪还大的图

文章的核心：SCLC细胞株和肿瘤样本中的细胞相对其它类型的肺癌细胞表面MHC I型HLA-A、B、C和β2m的表达有着显著的下降

【自己加的】这可能是躲避CD8+ T细胞抗肿瘤免疫的潜在机制，近期两项ICPi without chemotherapy治疗SLC研究失败，可能也基于此，要知道SCLC还是高TMB

We have found markedly deficient expression of the class I major histocompatibility antigens HLA-A,B,C and beta 2m on human small-cell lung cancer (SCLC) lines and fresh tumor samples. The deficit of HLA- A,B,C and beta 2-microglobulin (beta 2m) antigen expression was demonstrated with both radiobinding assays and indirect immunofluorescence assays. Immunoprecipitation of metabolically labeled cells with antibodies to class I antigens showed most SCLC lines to have synthesized almost no beta 2m and HLA-A,B,C proteins. Northern blot analysis, using human HLA-A,B, and beta 2m cDNA probes, showed that almost all SCLC lines tested had markedly decreased amounts of HLA and beta 2m mRNA, but both gene products could be induced with interferon treatment of SCLC lines. We conclude that human SCLC, in contrast to other lung cancer types, is characterized by greatly reduced transcription of HLA-A,B,C and beta 2m genes, which suggests the existence of a mechanism for evading the host immune response to the tumor and of an E1a-like product in this type of tumor cell.

后来发现NSCLC里也是这样：

TAP-1/-2负责将MHC I呈递的抗原肽转运到高尔基体最终运送到肿瘤细胞表面最终引发T细胞肿瘤免疫，这篇文献在93份手术切除的NSCLC样本中发现，38%完全缺失class I 分子，伴随着缺失轻链（β-2m）和重链A。另外8.3%和27%部分缺失选择性的缺失HLA-A基因座和A2等位基因。TAP-1的缺失通常伴随着重链A的缺失。因此抗原呈递复合物的缺失在肺癌中应该是一个常见事件。

 loss的MOA可能是HLA杂合性丢失（loss of heterozygosity，LOH）

编码HLA I类分子的等位基因分别来自父本和母本，有时基因变化能够导致一套基因丢失（LOH）时，此时就有潜力促进免疫逃避。研究显示在40%的NSCLC细胞中都能观察到HLA LOH，其与较高的亚克隆新抗原负荷、APOBEC介导的突变、细胞溶解活性上调和PD-L1阳性相关联。HLA LOH的亚克隆发生率、在肿瘤转移位点上的富集以及作为平行事件发生都提示着HLA LOH是一种免疫逃避机制，是在NSCLC肿瘤进化后期筛选出来的。