Abstract 4160: Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma
Authors: Kato Takuya , Noma Kazuhiro , Katsura Yuki , Kashima Hajime , Ninomiya Takayuki , Ohara Toshiaki , Tazawa Hiroshi , Kagawa Shunsuke , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: July 2016

Backgrounds: Cancer associated fibroblasts (CAFs) are thought to play an essential role in cancer invasion, migration, metastasis, and tumor immunosuppression. However, there has been still a little evidence of the correlation of tumor immunosuppression and CAFs in human esophageal carcinoma. The other hand, as like rising of PD-1 antibody targeting therapy to tumor immunosuppression have been shown dramatic cure responses in melanoma and now ongoing to other malignancies. Tumor-infiltrating lymphocytes (TILs) are considered typically to represent a host immune response against carcinoma. In many types of tumors TILs have been shown their strong correlation to patient's clinicopathological features. In this study, we evaluated the prognostic correlation of CAFs and TILs, which are classified respectively in tumor-associated CD8+ cytotoxic T lymphocytes (CTL) and FoxP3+ regulatory T cells (Treg) in surgically resected esophageal carcinoma.

Materials and methods: Total 58 cases with esophageal carcinoma in our institution were evaluated for the presence of CAFs and TILs by immunohistochemistry. TILs of CTL and Treg were calculated each in the intratumoral and the peripheral tissues, and the cutoff for subgroups was defined at the median value. CAFs were defined as fibroblasts expressing alpha smooth muscle actin (α-SMA), and evaluated with the α-SMA scoring by using “Area Index”, which is calculated by imageJ. TILs and CAFs were assessed for the associations with pathological invasion depth (pT), lymph node metastases (pN), histological types, and disease-free survival (DFS) or overall survival (OS).

Result: In intratumoral tissues, Treg was significantly associated with advanced T stages, and Treg and a CTL/Treg ratio were associated with lymph node metastasis. Higher CTL, higher CTL/Treg ratio and lower Treg were significantly associated with improved DFS and OS in univariate analysis. Furthermore, multivariate analysis demonstrated selected higher CTL as an independent prognostic factor (P = 0.010). On the other hand, in peripheral tissues, CTL, Treg, and CTL/Treg ratio were not correlated with clinicopathological factors or the any prognosis. Additionally the overexpression of CAFs was strongly associated with poor prognosis (P = 0.002) and the “Area Index” of α-SMA was inversely correlated with the CTL and CTL/Treg ratio in intratumoral tissues (P = 0.029, 0.017). It suggests that CAFs accumulation in tumor tissue is correlated to status of intratumoral immunesuppression.

Conclusion: The CTL in intratumoral tissues are independent prognostic factors, and are considered to play an essential role in tumor immunity. Our results demonstrate that CAFs are significant correlation of immunosuppression in esophageal carcinoma. In the future, targeting CAFs therapy itself might improve tumor immunosuppression, and there is possibility to prolong a prognosis.

Citation Format: Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hajime Kashima, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4160.