Li Xingru, Ling Agnes, Kellgren Therese G, Lundholm Marie, Löfgren-Burström Anna, Zingmark Carl, Rutegård Martin, Ljuslinder Ingrid, Palmqvist Richard, Edin Sofia
Department of Medical Biosciences, Pathology, Umeå University, 90185 Umeå, Sweden.
Department of Surgical and Perioperative Sciences, Surgery, Umeå University, 90185 Umeå, Sweden.
Cancers (Basel). 2020 Nov 19;12(11):3440. doi: 10.3390/cancers12113440.
The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1 T cells. No correlation was, however, found between MSI and the fraction of CTLA-4 T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1 T cells, but also CTLA-4 T cells. Furthermore, no correlation was found between PD-1 and CTLA-4 T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.
局部抗肿瘤免疫反应在结直肠癌（CRC）中具有重要的预后价值。在免疫治疗时代，更好地了解CRC分子亚组中的免疫反应可能会推动个性化医疗取得重大进展。就此而言，微卫星不稳定（MSI）肿瘤的特征是免疫浸润增加，这表明MSI可作为免疫抑制剂检查点治疗的标志物。在此，我们使用流式细胞术对69例CRC患者队列的肿瘤组织、相邻非恶性组织和血液中的免疫活性谱进行了全面分析。我们发现，与相邻非恶性组织相比，肿瘤中存在多种免疫抑制迹象，包括T细胞更常表达免疫检查点分子程序性细胞死亡蛋白（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）。我们进一步分析了CRC分子亚组中的免疫细胞浸润情况。确实发现MSI肿瘤与免疫浸润增加有关，包括PD-1 T细胞比例增加。然而，未发现MSI与CTLA-4 T细胞比例之间存在相关性。有趣的是，在微卫星稳定（MSS）肿瘤患者组中，一些患者也表现出免疫浸润增加，包括相当高比例的PD-1 T细胞，还有CTLA-4 T细胞。此外，未发现PD-1和CTLA-4 T细胞之间存在相关性，这表明不同肿瘤在一定程度上可能受不同免疫检查点的调节。我们进一步评估了CRC共识分子亚型中免疫活性谱的分布情况。总之，我们的研究结果表明，无论MSI状态如何，不同的免疫检查点抑制剂可能对特定的CRC患者有益。需要改进预测工具来识别这些患者。
