Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka City, Osaka Prefecture, 545-8585, Japan.
BMC Cancer. 2018 Apr 3;18(1):371. doi: 10.1186/s12885-018-4276-y.
The anticancer immune response has been reported to correlate with cancer progression. Tumor-infiltrating lymphocytes (TILs), which are one of the indicators of host immunity, affect the tumor growth, metastasis and chemoresistance. Both TILs in the primary tumor and those in the metastatic tumor have been reported to be a useful predictor of the survival and therapeutic outcome. However, the correlation between the density of TILs in the primary and metastatic tumor is unclear. The aim of this study was to elucidate the correlation between the density of TILs in the primary and metastatic tumor.
A total of 24 patients with stage IV colorectal cancer who underwent concurrent resection of the primary tumor and liver metastasis were enrolled in order to assess the correlation between the density of TILs in the primary tumor and that in the metastatic tumor. Hematoxylin and eosin (HE)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by the measurement of the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. In addition, to evaluate TIL subsets and the activation/suppression status of the lymphocytes, immunohistochemistry for CD4, CD8, Forkhead boxprotein P3 (FOXP3), programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), inducible T-cell co-stimulator (ICOS), Glucocorticoid induced tumor necrosis factor receptor related protein (GITR), Human Leukocyte Antigen - antigen D Related (HLA-DR) and Granzyme B was performed, and the number of immunoreactive lymphocytes was counted.
According to the evaluation using the HE-stained sections, the density of tumor-infiltrating mononuclear inflammatory cells in the primary tumor was significantly associated with that in the metastatic tumor. In addition, according to the immunohistochemistry evaluation, the density of CD4, CD8 and FOXP3 TILs in the primary tumor and that in the metastatic tumor were significantly correlated with that in the metastatic tumor. Furthermore, the activation/suppression marker values of the lymphocytes (i.e., such as PD-1, ICOS, Granzyme B and the PD-1/CD8 ratio) in the primary tumor were correlated with values in the metastatic tumor.
The local immune status of the primary tumor was revealed to be similar to that of the metastatic tumor. This suggests that the evaluation of the local immunity of the primary tumor may be a substitute for the evaluation of the local immunity of the metastatic lesion. Therefore, information on the primary tumor may be useful when considering treatment strategies for metastatic lesions.
抗肿瘤免疫反应已被报道与癌症进展相关。肿瘤浸润淋巴细胞（TILs）是宿主免疫的指标之一，影响肿瘤的生长、转移和化疗耐药性。原发肿瘤和转移瘤中的 TILs 均被报道为生存和治疗结果的有用预测指标。然而，原发和转移瘤中 TILs 密度之间的相关性尚不清楚。本研究旨在阐明原发和转移瘤中 TILs 密度之间的相关性。
共纳入 24 例接受原发肿瘤和肝转移同期切除术的 IV 期结直肠癌患者，以评估原发肿瘤和转移瘤中 TILs 密度之间的相关性。使用苏木精和伊红（HE）染色的肿瘤切片评估 TILs。通过测量单核炎性细胞在侵袭边缘的总基质面积中所占的面积来评估 TILs 密度。此外，为了评估 TIL 亚群和淋巴细胞的激活/抑制状态，进行了 CD4、CD8、叉头框蛋白 P3（FOXP3）、程序性细胞死亡 1（PD-1）、细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）、诱导型 T 细胞共刺激物（ICOS）、糖皮质激素诱导的肿瘤坏死因子受体相关蛋白（GITR）、人类白细胞抗原-D 相关（HLA-DR）和颗粒酶 B 的免疫组化染色，并对免疫反应性淋巴细胞的数量进行计数。
根据 HE 染色切片评估，原发肿瘤中浸润性单核炎性细胞的密度与转移瘤中浸润性单核炎性细胞的密度显著相关。此外，根据免疫组化评估，原发和转移瘤中 CD4、CD8 和 FOXP3 TILs 的密度与转移瘤中的密度显著相关。此外，原发肿瘤中淋巴细胞的激活/抑制标志物值（如 PD-1、ICOS、颗粒酶 B 和 PD-1/CD8 比值）与转移瘤中的值相关。
原发肿瘤的局部免疫状态与转移瘤相似。这表明原发肿瘤局部免疫的评估可能替代转移灶局部免疫的评估。因此，在考虑转移灶治疗策略时，原发肿瘤的信息可能有用。
