Background
Microsatellite instability (MSI)-high (MSI-H) colorectal cancer is known to be associated with increased tumor-infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response. Materials and
Conclusions
The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response. Implications for practice: This study demonstrates that the density of each subset of tumor-infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)-high and non-MSI-high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI-high (MSI-H) and non-MSI-H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI-high gastric cancer. 摘要 背景。众所周知，微卫星不稳定性 (MSI) 高 (MSI‐H) 的结直肠癌与肿瘤浸润淋巴细胞 (TIL) 的增加、宿主全身免疫应答升高以及预后良好有关。但是，很少通过TIL和全身免疫应答来评估胃癌的MSI状态。 材料和方法。我们评估了接受过MSI分型胃切除术的 345 名胃癌患者的数据。在用抗 CD3、CD4、CD8、叉头框 P3 (Foxp3) 和颗粒酶 B 进行免疫组织化学染色后，我们计算了TIL的数量，进而确定TIL亚群的数量。获得了白细胞分类计数和预后营养指数 (PNI)，以对全身免疫应答进行评估。 结果。在 345 名患者中，57 名患者患有 MSI‐H 肿瘤，288 名患者患有非 MSI‐H 肿瘤。MSI‐H 肿瘤携带更高密度的 CD8+ T 细胞、Foxp3+ T 细胞和颗粒酶 B+ T 细胞，以及更高比率的 Foxp3/CD4 和颗粒酶 B/CD8。TIL对 MSI‐H 肿瘤患者和非 MSI‐H 肿瘤患者的预后影响存在差异。未发现TIL是 MSI‐H 肿瘤组无复发生存期 (RFS) 或总生存期 (OS) 的重要预后因素。在非 MSI‐H 肿瘤组中，多变量分析显示，分期、PNI和 CD4+ T 细胞是RFS的独立预后因素，而分期、PNI和 Foxp3/CD4 比率是OS的独立预后因素。 结论。全身/局部免疫应答与预后的关系因MSI状态而异。MSI状态引起的不同肿瘤特征和预后可能与微卫星不稳定性和随后的宿主免疫应答引起的免疫原性有关。 实践意义:本研究表明，肿瘤浸润淋巴细胞 (TIL) 各亚群的密度在 微卫星不稳定性高(MSI‐H) 肿瘤与非 MSI‐H 肿瘤之间存在差异。另外，MSI‐H 肿瘤组与非 MSI‐H 肿瘤组术前全身免疫应答状况和TIL的预后效果也存在差异。本研究可能有助于确定癌症进展的机制，以及制定MSI‐H的胃癌的治疗策略。
Methods
We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti-CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.
Results
Of the 345 patients, 57 demonstrated MSI-H tumors and 288 demonstrated non-MSI-H tumors. MSI-H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI-H tumors and those with non-MSI-H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence-free survival (RFS) or overall survival (OS) in the MSI-H tumor group. In the non-MSI-H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS. Conclusions: The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response. Implications for practice: This study demonstrates that the density of each subset of tumor-infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)-high and non-MSI-high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI-high (MSI-H) and non-MSI-H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI-high gastric cancer. 摘要 背景。众所周知，微卫星不稳定性 (MSI) 高 (MSI‐H) 的结直肠癌与肿瘤浸润淋巴细胞 (TIL) 的增加、宿主全身免疫应答升高以及预后良好有关。但是，很少通过TIL和全身免疫应答来评估胃癌的MSI状态。 材料和方法。我们评估了接受过MSI分型胃切除术的 345 名胃癌患者的数据。在用抗 CD3、CD4、CD8、叉头框 P3 (Foxp3) 和颗粒酶 B 进行免疫组织化学染色后，我们计算了TIL的数量，进而确定TIL亚群的数量。获得了白细胞分类计数和预后营养指数 (PNI)，以对全身免疫应答进行评估。 结果。在 345 名患者中，57 名患者患有 MSI‐H 肿瘤，288 名患者患有非 MSI‐H 肿瘤。MSI‐H 肿瘤携带更高密度的 CD8+ T 细胞、Foxp3+ T 细胞和颗粒酶 B+ T 细胞，以及更高比率的 Foxp3/CD4 和颗粒酶 B/CD8。TIL对 MSI‐H 肿瘤患者和非 MSI‐H 肿瘤患者的预后影响存在差异。未发现TIL是 MSI‐H 肿瘤组无复发生存期 (RFS) 或总生存期 (OS) 的重要预后因素。在非 MSI‐H 肿瘤组中，多变量分析显示，分期、PNI和 CD4+ T 细胞是RFS的独立预后因素，而分期、PNI和 Foxp3/CD4 比率是OS的独立预后因素。 结论。全身/局部免疫应答与预后的关系因MSI状态而异。MSI状态引起的不同肿瘤特征和预后可能与微卫星不稳定性和随后的宿主免疫应答引起的免疫原性有关。 实践意义:本研究表明，肿瘤浸润淋巴细胞 (TIL) 各亚群的密度在 微卫星不稳定性高(MSI‐H) 肿瘤与非 MSI‐H 肿瘤之间存在差异。另外，MSI‐H 肿瘤组与非 MSI‐H 肿瘤组术前全身免疫应答状况和TIL的预后效果也存在差异。本研究可能有助于确定癌症进展的机制，以及制定MSI‐H的胃癌的治疗策略。