Cytoplasmic Expression of P16 is Related to Low Infiltration of CD8+ T cell and Poor Prognosis in Digestive Neuroendocrine Carcinoma

Background and Aims: The aim of this study is to examine the predictive and prognostic value of cytoplasmic P16Ink4A (cP16) and poor infiltration of CD8+ T cell in primary digestive neuroendocrine carcinoma (dNEC). Methods: We retrospectively reviewed 86 cases of NEC and mixed NEC (all cases thereafter refer to NEC), which had primary sites in digestive system. Kaplan-Meier survival curves and log-rank test were used for the survival analysis. Bioinformatics analysis was performed to identify the P16-related pathways. Results: The expression frequency of P16 in dNEC and adjacent tissues was 81.4% and 19.3% respectively (p<0.0001). There was no difference in overall survival (OS) between dNEC patients with P16 positive or negative expression. However, there was a statistically lower OS in dNEC patients with cP16 expression than those without cP16 expression (p=0.050). In addition, cP16 expression was correlated with poor infiltration of intratumoral CD8+ T cells. Furthermore,we found that dNEC patients with two features of cP16 expression in tumor and poor infiltration of CD8+ T cells in intratumoral tissue showed more poor survival (p=0.0133) than patients with single feature alone respectively. Bioinformatics analysis suggested that EGR1 and HLA class I might be involved in the inhibitory effect of cP16 on intratumoral infiltrated T cells. Conclusions: Therefore, the cP16 and poor intratumoral infiltration of CD8+ T cells may serve as poor prognostic biomarkers in dNEC. CP16 expression is associated with decreased intratumoral infiltration of CD8+ T cells probably related to deregulation of EGR1/ HLA class I pathway.