Evaluation of triple negative breast cancer with heterogeneous immune infiltration

This research is the first one to measure differences in immune heterogeneity within the same patient, avoiding patients' inter-heterogeneity, for the study of potential casualties to the presence of infiltrating immune cells. This difference could be explained due to the tumor intrinsic characteristics (for example, their HLA -human leukocyte antigen- phenotype having different affinity for antigens). However, here we have shown that it may depend also on the tumor heterogeneity. Secretion of different proteins and enzymes, transcriptional alterations, and expression of different regulatory genes and oncogenes by the tumor cells can lead to immune recognition and infiltration in some areas but not in others. This observation is reflected in the differential expression analysis in each patient as well as in the gene set enrichment analysis, in which, on top of the upregulation of the immune pathways in the high TIL areas, there is an upregulation of other non-immune related pathways. We hypothesized that the differences in the gene expression between the two areas are due to intrinsic differences between the tumor cells of each area that evolve differently during tumor development. The team recommends future research with single cell sequencing in patients with the same characteristics.

本研究为首项针对同一患者体内免疫异质性差异进行量化的研究，旨在探究浸润免疫细胞的存在所引发的潜在机体损伤，同时规避了患者间异质性的干扰。此类差异可归因于肿瘤固有特征，例如其人类白细胞抗原（human leukocyte antigen, HLA）表型对抗原具有不同的亲和力。但本研究证实，该差异同样可能与肿瘤异质性相关。肿瘤细胞分泌的不同蛋白质与酶类、发生的转录改变，以及表达的不同调控基因与致癌基因，可导致免疫识别与浸润仅出现在部分肿瘤区域。该观测结果在单患者差异表达分析与基因集富集分析中均得到验证：在高肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes, TIL）区域，除免疫通路出现上调外，其他非免疫相关通路亦存在上调现象。本研究提出假设：两处区域的基因表达差异，源于肿瘤发育过程中演化路径不同的各区域肿瘤细胞所存在的固有差异。研究团队建议，未来可针对具有同类特征的患者开展单细胞测序相关研究。