肿瘤微环境相关因子与直肠癌新辅助化学治疗疗效和预后的相关性
| 作者: |
1张思宇,
2郗彦凤,
2步鹏,
3仝煦楠,
1徐菁
1 山西医科大学病理教研室，太原 030001 2 山西省肿瘤医院病理科，太原 030001 3 山西医科大学研究生学院，太原 030001 |
| 通讯: |
徐菁
Email: xujing@sxmu.edu.cn |
| DOI: | 10.3978/j.issn.2095-6959.2018.01.009 |
| 基金: | 山西省科技厅重点研发项目(201603 D321049)；山西省卫生和计划生育委员会科研课题(2014052)。 |
摘要
目的：观察直肠癌新辅助化学治疗(neoadjuvant chemotherapy，NAC)前后，肿瘤微环境中肿瘤浸润淋巴细胞(tumor-infiltrating lymphocytes，TILs)的CD4，CD8，叉头翼状螺旋转录因子(transcription factor fork head box P3，FOXP3)，细胞毒性T淋巴细胞抗原-4(cytotoxic T lymphocyte associated antigen-4，CTLA-4)和程序性死亡配体(programmed death ligand-1，PD-L1)的表达水平变化，探讨这些免疫标志物的表达水平与NAC疗效及预后的关系。方法：采用免疫组织化学的方法检测50例直肠癌患者NAC前后CD4+ TILs，CD8+ TILs，FOXP3+ TILs，CTLA-4+ TILs和PD-L1+ TILs的表达水平变化，分析以上指标的表达与临床治疗效果之间的关系，并采用Kaplan-Meier法及COX比例风险回归模型进行生存分析。结果：与直肠癌NAC前相比，NAC后CD4+ TILs和CD8+ TILs明显升高，差异有统计学意义(P=0.002，P=0.001)；而CTLA-4+ TILs和FOXP3+ TILs的差异则无统计学意义(P=0.094，P=0.068)。直肠癌中PD-L1在TILs和肿瘤细胞中的表达为阴性。直肠NAC后癌降期组CD4+ TILs和CD8+ TILs高于未降期组，差异有统计学意义(P=0.026，P=0.048)，FOXP3+ TILs和CTLA-4+ TILs差异无统计学意义。直肠癌中CD8+ TILs高表达者总生存率较好。结论：免疫系统可能是通过增加CD4+ TILs，CD8+ TILs来抑制直肠癌肿瘤的生长；N分期，CD4+ TILs，CD8+ TILs的表达水平是评估NAC效果的敏感指标；CD8+ TILs的表达水平与NAC患者的预后相关。
关键词：
新辅助化学治疗；直肠癌；肿瘤微环境
Correlation of tumor microenvironment related markers with the curative effect and prognosis of neoadjuvant chemotherapy of rectal cancer
CorrespondingAuthor: XU Jing Email: xujing@sxmu.edu.cn
DOI: 10.3978/j.issn.2095-6959.2018.01.009
Foundation: This work was supported by the Major Research and Development Project of Shanxi Science and Technology Department (201603 D321049); the Scientific Research Task of the Shanxi Health and Family Planning Commission (2014052), China.
Abstract
Objective: To observe the expression level of CD4, CD8, FOXP3, cytotoxic T lymphocyte associated antigen-4 (CTLA-4), programmed death ligand-1 (PD-L1) of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment before and after the neoadjuvant chemotherapy (NAC) of rectal cancer and to study the correlation of the expression of these immune markers with the curative effect and prognosis of NAC of rectal cancer. Methods: Immunohistochemical method was used to detect the 50 patients’ changes in expression levels of CD4+ TILs, CD8+ TILs, FOXP3+ TILs, CTLA-4+ TILs and PD-L1+ TILs in tumor microenvironment before and after NAC, and analyses were conducted on the relationship between the expression of these markers and clinical therapeutic effect; besides, Kaplan-Meier method and COX proportional hazard regression analysis were used in survival analysis. Results: Compared with before NAC, the expression level of CD4+ TILs and CD8+TILs showed an evident increase after NAC of rectal cancer, with the statistically significant differences (P=0.002, P=0.001), while there was no statistical difference in the expression level of CTLA-4+ TILs and FOXP3+ TILs before and after NAC (P=0.094, P=0.068). PD-L1 in TILs and tumor cells was negatively expressed in rectal cancer. After the NAC of rectal cancer, the expression levels of CD4+ TILs and CD8+ TILs in the descending group were higher than those in the non-descending group, with the statistically significant differences (P=0.026, P=0.048). There was no statistic difference in the expression level of CTLA-4+ TILs and FOXP3+ TILs before and after NAC. In addition, higher level CD8+ TILs showed a higher survival rate. Conclusion: Increasing the expression level of CD8+ TILs and CD4+ TILs by immune system can impede the growing progress of tumor. The N staging of rectal cancer, CD4+ TILs, CD8+ TILs are the sensitive indices of the NAC curative effect, and the prognosis of rectal cancer patients who receive the NAC before the surgery is associated with the expression level of CD8+ TILs.
Keywords：
neoadjuvant chemotherapy; rectal cancer; tumor microenvironment