The High Expression of Inhibitory Lymphoid Receptors after Preoperative Radiation Therapy Predicts Favorable Prognosis of Locally Advanced Rectal Cancer

Abstract

The combination of immune checkpoint blockade and radiotherapy (RT) is a promising treatment strategy. We analyzed the effect of preoperative RT on the inhibitory lymphoid receptors (PD-1, TIM-3, and LAG-3) and their variation after RT. We also evaluated the prognostic value of those proteins expression. The expression of PD-1, TIM-3, LAG-3, CD8, and CD3 was detected by immunohistochemistry on specimens of 76 rectal cancer patients following neoadjuvant treatment, in which 13 cases of pretreatment specimen were available. The expression of proteins was assessed as the percentage of positive cells. Cutoff Finder application was used to estimate the optimized cutoff point of expression levels. The variation of proteins expression was compared by paired t-test and Mann-Whitney U test analysis. Survival analyses were performed by Kaplan–Meier curves and Cox regression models. Receiving operating characteristic curve analysis was conducted to develop the predictor of disease progression. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after RT (P = 0.043, 0.039). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (P = 0.011, 0.000). Interestingly, the level of ICs TIM-3 was lower for patients with >8 weeks interval after RT (P = 0.045). High level of those inhibitory lymphoid receptors appeared a favorable disease-free survival (DFS). PD-1 and IC TIM-3 were both the independent prognosis factors for DFS. Furthermore, IC TIM-3high and CD8high might improve the predicted sensitive of disease progression by adding to tumor regression grade (TRG) (P = 0.0068). RT had improved the expression of PD-1 and ICs LAG-3, while TIM-3 was inhibited. In addition, high expression of PD-1, TIM-3, and LAG-3 indicated a favorable DFS, and IC TIM-3high CD8high predicted poor outcomes.