PD-1/PD-L1 Correlates With the Efficacy of the Treatment of Concurrent Chemoradiotherapy in Cervical Cancer

Abstract

Background: Cervical cancer (CC) is the third most common cancer worldwide, with high mortality rates. The programmed cell death 1 (PD-1)/(PD-1 ligand) PD-L1 has been reported to be an effective indicator in cancer development. In this study, we aim to explore the role of PD-1/PD-L1 in the evaluation of concurrent chemoradiotherapy (CCRT) efficacy and prognosis in CC patients.

Methods: We included 55 CC patients in this study. Immunohistochemistry and flow cytometry were employed to detect the expression of PD-1, T_reg cells, CD8, and CD68 in tumor tissues, and the contents of PD-1⁺ CD8⁺ T cells, PD-1⁺ CD4⁺ T cells, and PD-1⁺ T_reg cells in the peripheral blood. The relationships of these indexes with CCRT efficacy were measured by Spearman correlation analysis, overall survival (OS), and disease-free survival (DFS) of patients were analyzed by Kaplan-Meier estimator, and the diagnostic values of these indexes in CC were assessed by a receiver operating characteristic (ROC) curve.

Results: The clinical effectivity rate of CCRT was 89.10%. The positive expressions of PD-L1, T_reg cells, PD-1⁺ CD8⁺ T cells, PD-1⁺ CD4⁺ T cells, and PD-1⁺ T_reg cells were reduced after CCRT, while the CD8 and CD68 increased. All 7 indexes had diagnostic values in evaluating CCRT efficacy and were considered the influencing factors of OS, DFS, and the prognosis of CC patients.

Conclusion: These findings indicate that PD-1/PD-L1 may be a potential indicator for the efficacy evaluation of CCRT and the prognosis of CC. This study may offer potential targets for CC treatment.

Keywords: cervical cancer; concurrent chemoradiotherapy; prognosis; programmed cell death 1; programmed cell death 1 ligand.

Figure 1

CCRT suppresses PD-L1 and T_reg-cell expressions but improves CD8 and CD68 expressions. (A) Positive expressions of PD-L1 and T_reg are decreased, CD8 and CD68 are increased before and after CCRT is detected by immunohistochemistry (the original magnification is ×400). (B) Positive expression rates of PD-L1 and T_reg cells were decreased, but that of CD8 and CD68 elevated after CCRT; expression rates were the measurement data, and were expressed as mean and standard deviation, paired t-test was used for intragroup comparison; ^*p < 0.05, compared with the figures after CCRT. CCRT, concurrent chemoradiotherapy; PD-L1, programmed death ligand 1.

Figure 2

PD-L1, T_reg cells, CD8, and CD68 expressions are associated with the efficacy of CCRT. Spearman’s correlation analysis indicates that expressions of PD-L1, T_reg cells, CD8, and CD68 are correlated with curative effect; CR + PR: n = 49; SD + PD: n = 6; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PD-L1, programmed death ligand 1; CCRT, concurrent chemoradiotherapy.

Figure 3

After CCRT, PD-L1 and T_reg expressions were inhibited in tumor tissues of patients with good treatment response, while CD8 and CD68 expressions were increased; the above situation was reversed in patients with poor treatment response.

Figure 4

CCRT lessens PD-1⁺ CD8⁺ T cells, PD-1⁺ CD8⁺ T cells, PD-1⁺ CD4⁺ T cells, and PD-1⁺ T_reg cells in peripheral blood detected by flow cytometry. Panel A, PD-1⁺ CD8⁺ T cells in peripheral blood decreased after CCRT detected by immunohistochemistry; Panel B, PD-1⁺ CD4⁺ T cells in peripheral blood decreased after CCRT detected by immunohistochemistry; Panel C, PD-1⁺ Treg cells in peripheral blood decreased after CCRT detected by immunohistochemistry; measurement data were expressed as mean and standard deviation and analyzed by paired t test, n = 55; (**** p<0.0001), compared with before CCRT; CCRT, concurrent chemoradiotherapy; PD-1, programmed death 1.

Figure 5

Contents of PD-1⁺ CD8⁺ T cells, PD-1⁺ CD4⁺ T cells, and PD-1⁺ T_reg cells are related to the efficacy of CCRT. Panel A, Spearman correlation analysis indicates that content of PD-1⁺ CD8⁺ T cells is correlated with efficacy of CCRT; Panel B, Spearman correlation analysis indicates that content of PD-1⁺ CD4⁺ T cells is correlated with efficacy of CCRT; Panel C, Spearman correlation analysis indicates that content of PD-1⁺ Treg cells is correlated with efficacy of CCRT; CR + PR: n = 49; SD + PD: n = 6 ; PD-1, programmed death 1; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CCRT, concurrent chemoradiotherapy.

Figure 6

The ROC curves indicate that PD-1/PD-L1 is effective for the efficacy evaluation of CCRT in CC. (A–G) The ROC curves for PD-L1, T_reg, CD8, CD68, PD-1⁺ CD8⁺ T cells, PD-1⁺ CD4⁺ T cells, and PD-1⁺ T_reg. PD-L1, programmed death ligand 1; PD-1, programmed death 1; CC, cervical cancer; ROC, receiver operating characteristic.

Figure 7

Lowly expressed PD-L1, T_reg, PD-1⁺ CD8⁺ T, PD-1⁺ CD4⁺ T, and PD-1⁺ T_reg, and highly expressed CD8 and CD68 are related to higher one-year OS. Panels A, B, E–G, the Kaplan-Meier estimator shows that low expression of PD-L1, T_reg, PD-1⁺ CD8⁺ T, PD-1⁺ CD4⁺ T, and PD-1⁺ T_reg is related to high OS of CC patients; Panels C, D, the Kaplan-Meier estimator shows that high expression of CD8, CD68 is related to high OS of CC patients; compared with before CCRT; OS, overall survival; CC, cervical cancer; PD-L1, programmed death ligand 1; PD-1, programmed death 1.

Figure 8

Lowly expressed PD-L1, T_reg, PD-1⁺ CD8⁺ T, PD-1⁺ CD4⁺ T, and PD-1⁺ T_reg, and highly expressed CD8 and CD68 are associated with DFS of CC patients. Panels A, B, E–G, the Kaplan-Meier estimator shows that low expression of PD-L1, T_reg, PD-1⁺ CD8⁺ T, PD-1⁺ CD4⁺ T, and PD-1⁺ T_reg is related to high DFS of CC patients; Panels C, D, the Kaplan-Meier estimator shows that high expression of CD8, CD68 is related to high DFS of CC patients; compared with before CCRT; DFS, disease-free survival; CC, cervical cancer; PD-L1, programmed death ligand 1; PD-1, programmed death 1.