Table 3.
Clinical implications of exosomal PD-L1 in cancer diagnosis, prognosis, and immunotherapy response.
| Tumor type (n) | Aim | Outcome | Reference |
|---|---|---|---|
| Soluble PD-L1 | |||
| Melanoma (35) | To compare the serum concentration of soluble PD-L1 in melanoma patients and healthy donors and to explore the clinical significance of soluble PD-L1 in patients with melanoma on PD-1 blockade. | The level of soluble PD-L1 was elevated in metastatic melanoma patients when compared to healthy donors (P = 0.004). Higher baseline levels (≥1.4 ng/mL) of PD-L1 were associated with PD in patients treated with PD-1 blockade (P = 0.001). After 5 months of treatment with PD-1 blockade, a ≥1.5-fold increase in circulating PD-L1 level correlated to a PR (P = 0.007). | [29] |
| NSCLC (109) | To compare the mean level of circulating PD-L1 in NSCLC patients and healthy controls and to evaluate the association between the level of serum-derived soluble PD-L1 and the clinical characteristics of advanced NSCLC patients. | The mean level of PD-L1 in NSCLC patients (0.723 ± 0.081 ng/mL) was significantly higher when compared to healthy controls (0.565 ± 0.048 ng/mL) (P < 0.001). A cutoff value of 0.636 ng/mL distinguished patients in the high and low expression groups. Higher PD-L1 expression correlated to abdominal organ metastasis (P = 0.004). The median OS in patients of the low expression group (26.8 months) was longer than in the high group (18.7 months) (P < 0.001). | [102] |
| GC (80) | To compare the expression of circulating PD-L1 in advanced GC patients to healthy controls and to evaluate the association between serum-derived PD-L1 and the prognosis of patients with advanced gastric cancer. | The mean value of circulating PD-L1 level in GC patients (0.8928 ± 0.0900 ng/mL) was higher than in healthy controls (0.5899 ± 0.0617 ng/mL) (P = 0.006). A cutoff value of 0.5993 ng/mL distinguished GC patients in high and low upregulated PD-L1 groups (P = 0.04). The OS 5-year rate in the high PD-L1 group was 65.6% and 44.7% in the low group (P = 0.028). High soluble PD-L1 expression was associated with GC differentiation (P = 0.032) and the absence of lymph node metastasis (P = 0.041). | [103] |
| Exosomal PD-L1 | |||
| Melanoma (44) | To compare the level of plasma-derived exosomal PD-L1 in melanoma patients to healthy donors and to correlate the level of exosomal PD-L1 with the clinical response to pembrolizumab. | The level of exosomal PD-L1 was ∼5 times higher in patients with metastatic melanoma than in healthy donors (P = 0.0002). A cutoff value of 1.03 ng/mL of exosomal PD-L1 distinguished responders (low) from nonresponders (high) to pembrolizumab therapy (P = 0.0018). A fold change > 2.43 ng/mL in exosomal PD-L1 levels at weeks 3-6 after pembrolizumab correlated to prolonged PFS and OS up to 15 months after landmark (P = 0.00002), with a sensitivity of 80% and specificity of 89.47%. | [12] |
| HNSCC (40) | To evaluate the potential contributions of plasma-derived exosomal PD-L1 to disease activity in patients with HNSCC. | Higher percentages of exosomal PD-L1 were observed in patients with AD compared to NED (P < 0.0137). Patients with N1 disease had significantly higher percentages of exosomal PD-L1 than those who were N0 (P < 0.0008). Patients in stages III and IV had higher percentages of exosomal PD-L1 than patients in stage I/II (P < 0.0001). The average level of soluble PD-L1 in plasma was 53.6 pg/mL ± 50.8, which did not correlate to any clinicopathological data. | [64] |
| NSCLC (24) | To correlate the level of plasma-derived circulating exosomal PD-L1 to PD-L1 expression in tumor tissue of patients with NSCLC prior to surgical resection. | The number of PD-L1 positive exosomes strongly correlated with the level of PD-L1 expression in tumor tissue as measured by IHC (P = 0.0367). However, the proportion of PD-L1 positive exosomes from each patient varied between 10 and 70%. | [28] |
| PDAC (17) | To assess whether pancreatic carcinoma releases exosomal PD-L1 when compared to SCA and CP and whether the detection of such expression has diagnostic or prognostic value in PDAC patients. | The level of exosomal PD-L1 in patients' serum was not able to distinguish PDAC patients from CP patients. A cutoff value of >299 was used to distinguish positive or negative exosomal PD-L1 levels. Exosomal PD-L1 positivity was correlated to an unresectable tumor at the time of diagnosis (P = 0.01). The median postoperative survival of exosomal PD-L1-negative patients was significantly longer (17.2 months) than exosomal PD-L1-positive patients (7.8 months) (P = 0.043). | [105] |
| NSCLC (85) | To investigate the clinical significance of serum-derived exosomal PD-L1 in NSCLC and to explore the correlation between exosomal PD-L1 expression and PD-L1 expression in tumor tissue of NSCLC patients. | Levels of exosomal PD-L1 levels of stage I-II (15.90 ± 6.45 pg/mL) and III/IV NSCLC patients (21.10 ± 11.63 pg/mL) were considerably higher than that of healthy controls (15.91 ± 6.45 pg/mL) (P < 0.05 and P < 0.001, respectively). Higher levels of exosomal PD-L1 were associated with advanced tumor stage (II, III, IV, P = 0.012), tumor size > 2.5cm (P = 0.003), lymph node status N1-3 (P = 0.03), and M1 (P = 0.026). Exosomal-PD-L1 levels did not correlate to PD-L1 IHC profiles. | [104] |
| Melanoma (100) | To evaluate the use of plasma-derived exosomal PD-L1 of melanoma patients to predict immunotherapy response and clinical outcome and to study the association between exosomal PD-L1 expression, tumor PD-L1 IHC detection, and soluble PD-L1. | The mean level of exosomal PD-L1 (64.26 pg/mL) was higher when compared with soluble PD-L1 (30, 0.1 pg/mL) and tumor positivity (100 vs. 67%) at baseline. The baseline level of exosomal PD-L1 was not associated with any clinicopathological feature. In patients with PD after immunotherapy, exosomal PD-L1 increased significantly (85.90 ± 24.4 vs. 344.20 ± 70.30, P = 0.0002). Patients experiencing CR and PR showed a decrease in exosomal PD-L1 after PD-1 blockade (P = 0.001). A cutoff value < 100 showed that a decrease in exosomal PD-L1 was associated with a better clinical outcome as measured by PFS and OS (P = 0.048 and 0.001, respectively). | [62] |
| GC (69) | To evaluate the prognostic value of plasma-derived exosomal PD-L1 in gastric cancer patients before surgery. | A cutoff value of 82.585 ng/mL of exosomal PD-L1 was used to analyze the correlations and survival analysis. OS was significantly lower in the high exosomal PD-L1 group than in the low group in patients with stage I and II (P = 0.004). Higher exosomal PD-L1 was associated with an advanced T stage (P = 0.028) and lymphatic invasion (P = 0.014). | [58] |
| NSCLC (25), SCLC (2), GC (1), HNSCC (3), CC (2), RCC (1), HCC (1), CHC (2), EC (5), DC (1) and melanoma (1) | To investigate the role of plasma-derived exosomal PD-L1 as a predictive biomarker and to assess therapy efficacy with PD-1 blockade in a variety of cancer types. | Exosomal PD-L1 of the NR was significantly higher than the R before treatment (P = 0.010). In the NSCLC cohort, low levels of exosomal PD-L1 before PD-1 therapy correlated to prolonged PFS (2 vs. 8 months, P = 0.010). Exosomal PD-L1 and tumor burden decreased when the therapy was effective (P < 0.005). | [59] |
| Genomic exosomal PD-L1 | |||
| Melanoma (18), NSCLC (8) | To investigate the association between PD-L1 mRNA in plasma-derived exosomes and response to nivolumab and pembrolizumab treatment in patients with melanoma and NSCLC. | A higher number of exosomal PD-L1 mRNA (830.4 ± 231.3 copies per mL) before therapy was positively associated with CR and PR, compared to patients with SD (298.8 ± 97.2 copies per mL) or PD (204.0 ± 68.8 copies per mL). The number of mRNA copies per milliliters of exosomal PD-L1 mRNA decreased in patients with CR (242.5 ± 82.5, P = 0.016), while it increased in the case of PD (416.0 ± 87.8, P = 0.001). | [13] |
| Glioblastoma (21) | To correlate serum- and plasma-derived exosomal PD-L1 DNA to tumor burden in patients with glioblastoma. | Enrichment of circulating exosomal PD-L1 DNA distinguished healthy controls from glioblastoma patients, while it also correlated to tumor volume (P = 0.0025). There was also a positive correlation between the PD-L1 expression in glioblastoma tissue and circulating exosomal PD-L1 DNA (P = 0.01). | [15] |
PD: progressive disease; CR: complete response; PR: partial response; NR: nonresponders; R: responders; SD: stable disease; AD: advanced disease; NED: not established disease; OS: overall survival; PFS: progression-free survival; IHC: immunohistochemistry; NSCLC: non-small-cell lung cancer; HNSCC: head and neck squamous cell carcinoma; PDAC: pancreatic ductal adenocarcinoma; CP: chronic pancreatitis; SCA: serous cystadenoma of the pancreas; SCLC: small cell lung cancer; CC: colon cancer; HCC: hepatocellular carcinoma; RCC: renal cell carcinoma; CHC: cholangiocarcinoma; DC: duodenal carcinoma; EC: esophageal carcinoma; (n): number of patients.