PC4 Potentially Predicts Chemoradiation-Induced Antitumor Immunity in Esophageal Squamous Cell Carcinoma

Chemoradiotherapy (CRT) induces an antitumor immune response in esophageal squamous cell carcinoma (ESCC), and thereby has enormous potential by itself and in combination with immune checkpoint inhibitors (ICI). Our previous studies indicated that human positive cofactor 4 (PC4) was an independent predictor of poor survival in patients with ESCC or lung cancer who were treated with definitive chemoradiation, with a mechanism involving the enhancement of nonhomologous end joining (NHEJ)-mediated DNA repair. Due to the important role of double-strand DNA (dsDNA) in the antitumor immune response, the present study aims to investigate PC4 as a predictor of pathological response and antitumor immune response in ESCC patients who underwent neoadjuvant CRT. In ESCC, low PC4 expression levels have significant power to predict pCR. In particular, pCR is 61.2% in patients with low PC4 expression, but only 23.4% in patients with high PC4. Both disease-free survival (DFS) and overall survival (OS) are significantly longer for patients with low PC4 than for those with high PC4. In agreement with our previous finding that PC4 participates in NHEJ-mediated DNA repair, our further analysis indicates that the expression of PC4 is not only significantly negatively correlated with cyto-free dsDNA in postoperative specimens, but also with tumor-infiltrating CD8⁺T lymphocytes (CD8⁺TILs) and GZMB⁺CD8⁺TILs, suggesting a possible mechanism that high PC4 negatively regulates the antitumor response and therefore results in poor prognosis. Together, our findings demonstrate that low expression of PC4 is a potential biomarker for predicting the antitumor immune response to chemoradiation in patients with operable locally advanced ESCC.