Janikovits Jonas, Müller Meike, Krzykalla Julia, Körner Sandrina, Echterdiek Fabian, Lahrmann Bernd, Grabe Niels, Schneider Martin, Benner Axel, Doeberitz Magnus von Knebel, Kloor Matthias
Department of Applied Tumour Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Heidelberg, Germany, and Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg.
Division of Biostatistics, DKFZ (German Cancer Research Center), Heidelberg, Germany.
Oncoimmunology. 2017 Nov 6;7(2):e1390640. doi: 10.1080/2162402X.2017.1390640. eCollection 2018.
DNA mismatch repair (MMR)-deficient cancers accumulate high numbers of coding microsatellite mutations, which lead to the generation of highly immunogenic frameshift peptide (FSP) neoantigens. MMR-deficient cells can grow out to clinically manifest cancers either if they evade immune cell attack or if local T-cells get exhausted. Therefore, a subset of MSI cancer patients responds particularly well to treatment with immune checkpoint inhibitors. We analyzed whether immune evasion in MMR-deficient cancer mediated by loss of HLA class I or II antigens is related to local immune cell activation status. Microsatellites located in and the HLA class II-regulatory genes and were analyzed for mutations in MMR-deficient colorectal cancers (n = 53). The results were related to CD3-positive and PDCD1 (PD-1)-positive T-cell infiltration. PDCD1 (PD-1)-positive T-cell counts were significantly higher in -mutant compared to -wild type tumors (median: 22.2 cells per 0.25 mm vs. 2.0 cells per 0.25 mm, Wilcoxon test p = 0.002). Increasing PDCD1 (PD-1)-positive T-cell infiltration was significantly related to an increased likelihood of mutations (OR = 1.81). HLA class II antigen expression status was significantly associated with enhanced overall T-cell infiltration, but not related to PDCD1 (PD-1)-positive T-cells. These results suggest that immune evasion mediated by mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PDCD1 (PD-1)-positive T cell infiltration. If mutations interfere with anti-PDCD1 (PD-1)/CD274 (PD-L1) therapy success, we predict that resistance towards anti-PDCD1 (PD-1) therapy may - counterintuitively - be particularly common in patients with MMR-deficient cancers that show high PDCD1 (PD-1)-positive T cell infiltration.
DNA错配修复（MMR）缺陷型癌症会积累大量编码微卫星突变，这会导致产生高度免疫原性的移码肽（FSP）新抗原。如果MMR缺陷型细胞能够逃避免疫细胞攻击，或者局部T细胞耗竭，它们就会发展为临床上可表现的癌症。因此，一部分微卫星高度不稳定（MSI）癌症患者对免疫检查点抑制剂治疗反应特别良好。我们分析了由HLA I类或II类抗原缺失介导的MMR缺陷型癌症中的免疫逃逸是否与局部免疫细胞激活状态有关。对53例MMR缺陷型结直肠癌中位于 以及HLA II类调节基因 和 中的微卫星进行了突变分析。结果与CD3阳性和程序性死亡受体1（PDCD1，即PD-1）阳性T细胞浸润情况相关。与 野生型肿瘤相比， 突变型肿瘤中PDCD1（PD-1）阳性T细胞计数显著更高（中位数：每0.25平方毫米22.2个细胞 vs. 每0.25平方毫米2.0个细胞，Wilcoxon检验p = 0.002）。PDCD1（PD-1）阳性T细胞浸润增加与 突变可能性增加显著相关（比值比 = 1.81）。HLA II类抗原表达状态与整体T细胞浸润增强显著相关，但与PDCD1（PD-1）阳性T细胞无关。这些结果表明，由 突变诱导的HLA I类抗原表达缺失介导的免疫逃逸主要发生在激活的PDCD1（PD-1）阳性T细胞浸润环境中。如果 突变干扰抗PDCD1（PD-1）/CD274（PD-L1）治疗的成功，我们预测，与直觉相反，对抗PDCD1（PD-1）治疗的耐药性在显示高PDCD1（PD-1）阳性T细胞浸润的MMR缺陷型癌症患者中可能特别常见。
