Prognostic value of PD-L1 expression in combination with CD8+ TILs density in patients with surgically resected non-small cell lung cancer

Abstract

To investigate the prognostic value of PD-L1 expression combined with CD8⁺ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8⁺ TILs, and oncogenic alterations. PD-L1⁺ was detected in 71 (39.9%) and CD8^high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR^- were associated with both PD-L1⁺ and CD8^high TILs. Patients with CD8^high TILs had longer OS (P = 0.012). PD-L1^- was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8^high TILs (HR = 0.411; 95% CI, 0.177-0.954; P = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1⁺ /CD8^high and PD-L1⁺ /CD8^low , respectively (P = 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8^high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (P = 0.017 and 0.049, respectively). The combination of PD-L1 and CD8⁺ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

Keywords: CD8; non-small cell lung cancer; prognosis; programmed cell death ligand-1; tumor infiltrating lymphocytes.

Figure 1

The correlation between the expression levels of PD‐L1 (on tumor cells) or CD8⁺ TILs density and OS among NSCLC patients. CD8^high TILs was associated with better OS, but the expression levels of PD‐L1 showed no correlation with OS among NSCLC patients (A–C), patients with ADC (D–F), and solid ADC (G–I), respectively; in patients with SqCC (M–O), PD‐L1⁺ was associated with longer OS, but CD8⁺ TILs density showed no correlation with OS; on the contrary, in patients with non‐solid ADC (J–L), PD‐L1^– may suggest favorable OS, and patients with PD‐L1^low reached the longest OS, but CD8⁺ TILs density showed no correlation with OS.

Figure 2

Survival analysis of p‐stage I/II NSCLC patients based on the expression levels of PD‐L1 (on tumor cells), CD8⁺ TILs density and the combination of PD‐L1 expression (5% cut‐off) and CD8⁺ TILs density (5% cut‐off). As for p‐stage I/II NSCLC patients, the expression levels of either PD‐L1 or CD8 was not associated with OS, not even the combination of both.

Figure 3

Kaplan–Meier survival curves of patients with NSCLC (A), ADC (B), solid ADC (C), non‐solid ADC (D), and SqCC (E) sub‐grouped by the combination of PD‐L1 expression (5% cut‐off) and CD8⁺ TILs density (5% cut‐off). Significant statistical differences were shown in patients with NSCLC, ADC and non‐solid ADC (P = 0.025, 0.010 & 0.026, respectively). In patients with ADC and non‐solid ADC, patients with PD‐L1^–/CD8^high had the longest OS, and PD‐L1⁺/CD8^low had the shortest OS. However, among the whole NSCLC patients, patients with PD‐L1⁺/CD8^high had the longest OS, and PD‐L1^–/CD8^low had the shortest OS. No statistical differences were shown in patients with solid ADC and SqCC.

Figure 4

The correlation between the expression levels of PD‐L1 (on tumor cells) or CD8⁺ TILs density and OS among NSCLC patients with diverse ODM status. In NSCLC patients with EGFR ⁺ (A–C) and KRAS ⁺ (G–I), no statistical differences were shown. In NSCLC patients with EGFR ^– (D–F) and KRAS ^– (J–L), patients with CD8^high had longer OS than those with CD8^low (P = 0.047 & 0.039, respectively). In patients with ODM⁺ (M–O) and ODM^– (P–R), it showed no correlation between CD8⁺ TILs density and OS; PD‐L1 expression (5% cut‐off) was associated with OS in both groups of patients: ODM⁺ patients with PD‐L1^– had longer OS (P = 0.047), meanwhile, ODM^– patients with PD‐L1⁺ had longer OS (P = 0.048).

Figure 5

(A) Bar chart showing the quantity of cases of consistent/inconsistent expression of PD‐L1/CD8⁺ TILs between PLs and LNs; (B) Kaplan–Meier survival curves of patients with LN⁺ (A–C), consistent expression of PD‐L1 (between PLs and LNs) (D–F), inconsistent expression of PD‐L1 (G–I), consistent expression of CD8⁺ TILs density (J–L), inconsistent expression of CD8⁺ TILs density (M–O). Other than patients with inconsistent expression of PD‐L1, CD8^high TILs was associated with better OS than CD8^low in the rest four groups. It showed no correlation between PD‐L1 expression and OS among all the five groups. Notes: LN⁺ refers to metastatic lymph nodes (patients staged as p‐TxN1‐3Mx). PLs, primary lesions; LNs, lymph nodes.