PDF(Pubmed)
Abstract：
Clear cell renal cell carcinoma (ccRCC) is an immunologically vulnerable tumor entity, and immune checkpoint inhibitors are now widely used to treat patients with advanced disease. Whether and to what extent immune responses in ccRCC are shaped by genetic alterations, however, is only beginning to emerge. In this proof-of-concept study, we performed a detailed correlative analysis of the mutational and immunological landscapes in a series of 23 consecutive kidney cancer patients. We discovered that a high infiltration with CD8 + T cells was not dependent on the number of driver mutations but rather on the presence of specific mutational events, namely pathogenic mutations in PTEN or BAP1. This observation encouraged us to compare mechanisms of T cell suppression in the context of four different genetic patterns, i.e., the presence of multiple drivers, a PTEN or BAP1 mutation, or the absence of detectable driver mutations. We found that ccRCCs harboring a PTEN or BAP1 mutation showed the lowest level of Granzyme B positive tumor-infiltrating lymphocytes (TILs). A multiplex immunofluorescence analysis revealed a significant number of CD8 + TILs in the vicinity of CD68 + macrophages/monocytes in the context of a BAP1 mutation but not in the context of a PTEN mutation. In line with this finding, direct interactions between CD8 + TILs and CD163 + M2-polarized macrophages were found in BAP1-mutated ccRCC but not in tumors with other mutational patterns. While an absence of driver mutations was associated with more CD8 + TILs in the vicinity of FOXP3 + Tregs and CD68 + monocytes/macrophages, the presence of multiple driver mutations was, to our surprise, not found to be strongly associated with immunosuppressive mechanisms. Our results highlight the role of genetic alterations in shaping the immunological landscape of ccRCC. We discovered a remarkable heterogeneity of mechanisms that can lead to T cell suppression, which supports the need for personalized immune oncological approaches.
摘要：
透明细胞肾细胞癌（ccRCC）是一种免疫脆弱的肿瘤实体，和免疫检查点抑制剂现在广泛用于治疗晚期疾病患者。ccRCC中的免疫反应是否以及在多大程度上是由遗传改变形成的，然而,才刚刚开始出现。在这个概念验证研究中,我们对一系列23例连续肾癌患者的突变和免疫状况进行了详细的相关分析.我们发现CD8+T细胞的高浸润不依赖于驱动突变的数量，而是依赖于特定突变事件的存在。即PTEN或BAP1中的致病性突变。这一观察结果鼓励我们在四种不同的遗传模式的背景下比较T细胞抑制的机制，即，多个司机的存在，PTEN或BAP1突变，或不存在可检测的驱动突变。我们发现具有PTEN或BAP1突变的ccRCC显示出最低水平的颗粒酶B阳性肿瘤浸润淋巴细胞（TIL）。多重免疫荧光分析显示，在BAP1突变的情况下，但在PTEN突变的情况下，CD68巨噬细胞/单核细胞附近有大量CD8TIL。根据这一发现，在BAP1突变的ccRCC中发现了CD8TIL和CD163M2极化的巨噬细胞之间的直接相互作用，但在具有其他突变模式的肿瘤中未发现。虽然缺乏驱动突变与FOXP3+Tregs和CD68+单核细胞/巨噬细胞附近更多的CD8+TIL相关，存在多个驱动突变，令我们惊讶的是，未发现与免疫抑制机制密切相关。我们的结果强调了遗传改变在塑造ccRCC免疫学景观中的作用。我们发现了可以导致T细胞抑制的机制的显着异质性，这支持了对个性化免疫肿瘤方法的需求。
