肿瘤细胞治疗研究
英文原题：Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment.
Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment.
PD-L1/2表达的临床病理意义可能因TME状态而异。免疫检查点抑制剂可能改善FoxP3/CD8比值低且PD-L2表达的SBA患者的预后。
综合基因组分析显示，小肠腺癌（SBA）具有与胃癌和结直肠癌不同的基因组图谱。因此，基于SBA特征建立化疗方案至关重要。程序性细胞死亡配体1（PD-L1）和程序性细胞死亡配体2（PD-L2）在SBA中的表达尚未完全明确。抗PD-L1/PD-1治疗利用TIL（肿瘤浸润淋巴细胞）（TILs）；因此，肿瘤微环境（TME）中TILs的状态可能影响其疗效。据报道，FoxP3+与CD8+ T细胞的比值可用于预测消化系统癌症的预后。
探讨SBA组织中PD-L1/2表达根据TILs状态的临床病理意义。
我们对50例诊断为原发性SBA患者的福尔马林固定、石蜡包埋组织进行了PD-L1、PD-L2、CD8、FoxP3和DNA错配修复（MMR）蛋白的免疫组化分析。PD-L1和PD-L2的免疫反应性分别在肿瘤细胞和肿瘤浸润免疫细胞中于整个肿瘤中心和浸润边缘进行测定，最终采用联合阳性评分（CPS）进行评估。我们评估了瘤内和肿瘤周围间质中的CD8+和FoxP3+ T细胞。随后，我们计算并汇总了FoxP3与CD8+ T细胞计数的比值。免疫相关细胞密度分为低或高。将免疫组化结果与临床病理因素和患者预后进行比较。采用Kaplan-Meier法估计癌症特异性生存（CSS）的分布，并使用log-rank检验检测CSS的显著差异。还使用Cox比例风险模型评估肿瘤变量对CSS的影响。
在受检病例中，肿瘤细胞PD-L1（T-PD-L1）表达阳性率为34%，肿瘤浸润免疫细胞PD-L1（I-PD-L1）表达阳性率为54%。T-PD-L2阳性率为34%，I-PD-L2阳性率为42%。PD-L1 CPS ≥ 10和PD-L2 CPS ≥ 10分别见于50%和56%的病例。错配修复缺陷（dMMR）占14%。T-PD-L1、I-PD-L1和PD-L1 CPS ≥ 10均与dMMR显著相关（分别为P = 0.037、P = 0.009和P = 0.005）。T-PD-L1、I-PD-L1和PD-L1 CPS ≥ 10均与更深的浸润深度相关（分别为P = 0.001、P = 0.024和P = 0.002）。I-PD-L2表达和PD-L2 CPS ≥ 10在分化型组织学类型中显著更高（分别为P = 0.015和P = 0.030）。I-PD-L1和I-PD-L2水平与更好的CSS显著相关（分别为P = 0.037和P = 0.015）。CD8高表达与较少的淋巴结转移（P = 0.047）、较少的远处转移（P = 0.024）、较少的腹膜播散（P = 0.034）和较早的TNM分期（P = 0.047）显著相关。CD8高表达组的预后优于CD8低表达组（P = 0.018）。FoxP3表达与任何临床病理因素或预后均无关。我们发现，在FoxP3/CD8低表达组中，PD-L2 CPS ≥ 10的患者倾向于预后更差（P = 0.088）。
BACKGROUND: Comprehensive genomic analysis has shown that small bowel adenocarcinoma (SBA) has different genomic profiles from gastric and colorectal cancers. Hence, it is essential to establish chemotherapeutic regimens based on SBA characteristics. The expression of programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2) in SBA is not fully understood. Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes (TILs); therefore, the status of TILs in the tumor microenvironment (TME) may influence their efficacy. The ratio of FoxP3+ to CD8+ T cells has been reported to be useful in predicting the prognosis of digestive system cancers. AIM: To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues. METHODS: We performed immunohistochemical analysis for PD-L1, PD-L2, CD8, FoxP3, and DNA mismatch repair (MMR) proteins using formalin-fixed, paraffin-embedded tissues from 50 patients diagnosed with primary SBA. The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins, and finally evaluated using the combined positive score (CPS). We assessed CD8+ and FoxP3+ T cells in the intratumoral and tumor-surrounding stroma. Subsequently, we calculated and summed the ratio of FoxP3 to CD8+ T cell counts. Immune-related cell densities were graded as low or high. Immunohistochemical results were compared with clinicopathological factors and patient prognosis. The distribution of cancer-specific survival (CSS) was estimated using the Kaplan-Meier method, and the log-rank test was used to test for significant differences in CSS. A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS. RESULTS: PD-L1 expression was positive in 34% in tumor cells (T-PD-L1) and 54% in tumor-infiltrating immune cells (I-PD-L1) of the cases examined. T-PD-L2 was positive in 34% and I-PD-L2 was positive in 42% of the cases. PD-L1 CPS ≥ 10 and PD-L2 CPS ≥ 10 were observed in 50% and 56% of the cases, respectively. Deficient MMR (dMMR) was 14% of the cases. T-PD-L1, I-PD-L1 and PD-L1 CPS ≥ 10 were all significantly associated with dMMR ( P = 0.037, P = 0.009, and P = 0.005, respectively). T-PD-L1, I-PD-L1, and PD-L1 CPS ≥ 10 were all associated with deeper depth of invasion ( P = 0.001, P = 0.024, and P = 0.002, respectively). I-PD-L2 expression and PD-L2 CPS ≥ 10 were significantly higher in the differentiated histological type ( P = 0.015 and P = 0.030, respectively). The I-PD-L1 and I-PD-L2 levels were significantly associated with better CSS ( P = 0.037 and P = 0.015, respectively). CD8-high was significantly associated with less lymph node metastasis ( P = 0.047), less distant metastasis ( P = 0.024), less peritoneal dissemination ( P = 0.034), and earlier TNM stage ( P = 0.047). The CD8-high group had better prognosis than the CD8-low group ( P = 0.018). FoxP3 expression was not associated with any clinicopathological factors or prognosis. We found that patients with PD-L2 CPS ≥ 10 tended to have worse prognosis in the FoxP3/CD8-low group ( P = 0.088). CONCLUSION: The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status. Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.
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