[Prognostic value of tumor infiltration immune cells in pancreatic cancer]

Objective: To investigate the prognostic effect of tumour-infiltrating immune cell, including CD8(+) T cell, regulatory T-cell (Treg) and myeloid-derived suppressor cells (MDSC) on pancreatic patients. Methods: This study retrospectively collected the data of 80 patients who were histologically diagnosed of pancreatic cancer and underwent classical R0 surgical resection at Tianjin Medical University Cancer Institute and Hospital from January 2010 to May 2012. All patients survival were followed up until the cut-off date of January 2015. Clinicopathological features including immunohistochemical staining of FOXP3, CD8 and CD33 were reviewed as indice for evaluating the prognosis of pancreatic patients.The prognostic effect of tumour-infiltrating immune cells were analysed by Kaplan-Meier and Log-rank test. Multiple-factor analysis was conducted with the Cox regression model. The correlation between tumour-infiltrating immune cells and clinicopathological features was analysed by χ(2) test. The C57BL/6 mouse model was used to evaluate the efficacy of Treg and MDSC depletion therapy in vivo. Student's t-test was applied to assess the difference of the tumour volume, Ki-67 positive rate and CD8(+) T-cell infiltration proportion between depletion group and control group. Results: Eventually, 80 patients were included and no patient was lost during the follow-up period. The median follow-up time was 33.2 months (7.4-59.9 months). Patients with high level of tumour-infiltrating CD8(+) T cells had longer overall survival (OS) time ((21.6±11.9)months vs. (13.6±7.4)months, χ(2)=4.647, P = 0.031) than those with low level of tumour-infiltrating CD8(+) T cells. Tumor infiltration FOXP3(+) cells were strongly associated with reduced OS((20.9±8.5)months vs.(13.4±8.8)months, χ(2)=10.528, P=0.001), reduced relapse free survival (RFS) ((15.2±9.0)months vs. (9.5±8.8)months, χ(2)=6.288, P=0.012) and larger tumor size(χ(2)=4.073, r=0.226, P=0.044). The high intratumoural MDSC group showed a significantly shorter OS((23.5±11.8)months vs. (13.8±7.6)months, χ(2)=5.724, P=0.017), RFS((17.9±11.3)months vs. (10.2±7.5)months, χ(2)=7.430, P=0.006) and more advanced N stage (χ(2)=4.714, r=0.243, P=0.030) than the low intratumoural MDSC group. Multivariate Cox analysis revealed that pTNM (P=0.008), tumour-infiltrating Treg density (P=0.009) and intratumoural MDSC density (P=0.034) were independent and negative prognostic factors for OS; pTNM(P=0.003) and tumour-infiltrating MDSC level(P=0.018) were independent and negative factors for RFS. The experiment in vivo revealed that Treg and MDSC depletion therapy significantly decreased tumour volume in the C57BL/6 mouse model of subcutaneous tumours((1 396.3±442.5)mm(3) vs. (3 356.9±533.5)mm(3), t=4.986, P=0.018). Tumour Ki-67 positive rate significantly decreased (23%±5% vs. 55%±10%, t=3.130, P=0.011) in Treg and MDSC depletion group, whereas, the proportion of tumour-infiltrating CD8(+) T cells significantly increased in depletion groups (3.25%±0.69% vs. 0.76%±0.25%, t=3.393, P=0.007). Conclusions: Tumour-infiltrating Treg, MDSC level and pTNM stage are independent prognostic factors for patients with pancreatic cancer. Treg and MDSC depletion therapy can significantly retard tumour growth and increase the level of tumour-infiltrating CD8(+) T-cells in the C57BL/6 mouse model of subcutaneous tumours.