Department of Immunology, Weizmann Institute of Science Rehovot, Israel.
Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
Front Immunol. 2019 Feb 18;10:141. doi: 10.3389/fimmu.2019.00141. eCollection 2019.
Antigen presentation on HLA molecules is a major mechanism by which the immune system monitors self and non-self-recognition. Importantly, HLA-I presentation has gained much attention through its role in eliciting anti-tumor immunity. Several determinants controlling the peptides presented on HLA have been uncovered, mainly through the study of model substrates and large-scale immunopeptidome analyses. These determinants include the relative abundances of proteins in the cell, the stability or turnover rate of these proteins and the binding affinities of a given peptide to the HLA haplotypes found in a cell. However, the regulatory principles involved in selection and regulation of specific antigens in response to tumor pro-inflammatory signals remain largely unknown. Here, we chose to examine the effect that TNFα and IFNγ stimulation may exert on the immunopeptidome landscape of lung cancer cells. We show that the expression of many of the proteins involved in the class I antigen presentation pathway are changed by pro-inflammatory cytokines. Further, we could show that increased expression of the HLA-B allomorph drives a significant change in HLA-bound antigens, independently of the significant changes observed in the cellular proteome. Finally, we observed increased HLA-B levels in correlation with tumor infiltration across the TCGA lung cancer cohorts. Taken together, our results suggest that the immunopeptidome landscape should be examined in the context of anti-tumor immunity whereby signals in the microenvironment may be critical in shaping and modulating this important aspect of host-tumor interactions.
HLA 分子上的抗原呈递是免疫系统监测自我和非自我识别的主要机制。重要的是，HLA-I 呈递因其在引发抗肿瘤免疫中的作用而受到广泛关注。已经发现了几种控制 HLA 上呈现肽的决定因素，主要是通过对模型底物和大规模免疫肽组分析的研究。这些决定因素包括细胞中蛋白质的相对丰度、这些蛋白质的稳定性或周转率以及给定肽与细胞中发现的 HLA 单倍型的结合亲和力。然而，与肿瘤促炎信号反应中特定抗原的选择和调节相关的调节原则在很大程度上仍然未知。在这里，我们选择研究 TNFα 和 IFNγ 刺激可能对肺癌细胞免疫肽组景观产生的影响。我们表明，许多参与 I 类抗原呈递途径的蛋白质的表达被促炎细胞因子改变。此外，我们可以表明 HLA-B 同种异型的表达增加会导致 HLA 结合抗原发生显著变化，而与细胞蛋白质组中观察到的显著变化无关。最后，我们观察到 HLA-B 水平的增加与 TCGA 肺癌队列中的肿瘤浸润呈正相关。总之，我们的研究结果表明，在抗肿瘤免疫的背景下应该检查免疫肽组景观，其中微环境中的信号可能对塑造和调节宿主-肿瘤相互作用的这一重要方面至关重要。
