Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer (CRC) with poor prognosis, and is also considered as model to study the change of CRC from pre-tumor to tumor progression. To better predict and guide clinical applications of immune check point inhibitors(ICI), researchers proposed the classification system of human cancer, termed tumor immunity in the microenvironment (TIME), that four different TIME groups have been identified according to the presence of TILs and B7-H1(PD-L1) expression in tumor biopsies. Therefore, we followed and performed this theory into our research about TIME of FAP, to explore the potential of immunotherapy for FAP, and explore the cancerous mechanism from immune microenvironment.
We collected tissue samples of 40 FAP patients from May 2009 to December 2018, followed by detection of PD-L1 by using Dako PD-L1 IHC 22C3 pharmDx, MLH1, PMS2, MSH2, MSH6 were detected by IHC, and CD8+ T cells, tumor associated macrophages (TAM) and NK cells infiltration in the tumor biopsies by multiple fluorescence immunohistochemistry (mICH). Follow-up data of these 40 patients were analyzed.
CD8+T cells, M1 and M2 TAM, CD56bright NK and CD56dim NK cells were found both in intratumoral region and tumor rim of FAP patients(n=40), no differences have been found between M1and M2 TAM, however, CD56dim NK increased more than CD56bright NK both in intratumoral region and tumor rim(p<0.01). Surprisingly, no positive expression of PD-L1 was detected in the tumor tissue of these FAP patients (Tumor Proportion Score, TPS<1%). Further results shown CD56dim NK mainly increased in the tissue of FAP patients(n=7) with loss of MLH1, and consistent with this, these patients shown better prognosis than patients with wild type MLH1, that is, have longer progression free survival (p<0.005).
For the TIME characteristics of FAP patient, Immunotherapy targeted PD-1/PD-L1 may not applicable for FAP, however, MLH1, the member of mismatch repair protein, was associated with infiltration of NK cells, especially CD56dim NK cells in the tumor, and also associated with prognosis of FAP patients. Therefore, it can be exploited as potential target of immunotherapy for FAP or even CRC.
Citation Format: Jun Yang, Hushan Zhang, Wei Qing Liu, Wenliang Li, Shumin Ma, Lei Liang, Zhiyong Kou, Depei Huang, Xudong Shen, Jian Dong. Infiltration of CD56dim NK cells regulated by MLH1 into tumor tissue of FAP patients predict better prognosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3871.