Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
Oncologist. 2019 Sep;24(9):e835-e844. doi: 10.1634/theoncologist.2018-0273. Epub 2019 Mar 20.
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.
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.
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.
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.
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.
微卫星不稳定性（MSI）高的结直肠癌已知与肿瘤浸润淋巴细胞（TILs）增加、宿主全身免疫反应升高和预后良好相关。然而，在胃癌中，MSI 状态很少在 TILs 和全身免疫反应的背景下进行评估。
我们评估了 345 名接受 MSI 分型胃切除术的胃癌患者的数据。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，计算 TIL 的数量，以定量 TIL 的亚群。为了评估全身免疫反应，获得了白细胞分类计数和预后营养指数（PNI）的差异。
在 345 名患者中，57 名患者的肿瘤为 MSI-H，288 名患者的肿瘤为非 MSI-H。MSI-H 肿瘤的 CD8+T 细胞、Foxp3+T 细胞和颗粒酶 B+T 细胞密度显著更高，Foxp3/CD4 和颗粒酶 B/CD8 的比值更高。TILs 的预后影响在 MSI-H 肿瘤患者和非 MSI-H 肿瘤患者之间存在差异。在 MSI-H 肿瘤组中，TIL 亚群并不是无复发生存（RFS）或总生存（OS）的显著预后因素。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 比值是 OS 的独立预后因素。
根据 MSI 状态，全身/局部免疫反应与预后的关系不同。根据 MSI 状态不同的肿瘤特征和预后可能与微卫星不稳定性引起的免疫原性和随后的宿主免疫反应有关。
本研究表明，微卫星不稳定性（MSI）高和非 MSI 高肿瘤之间肿瘤浸润淋巴细胞（TILs）各亚群的密度不同。此外，术前全身免疫反应状态和 TILs 的预后作用在 MSI 高（MSI-H）和非 MSI-H 肿瘤组之间存在差异。本研究可能有助于确定癌症进展的机制，并为 MSI 高胃癌制定治疗策略。
