Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

Abstract

Background: Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been reported as possibly favorable prognostic factors in colorectal cancer (CRC). However, their longitudinal effect is unknown. Methods: A pilot study was performed to investigate whether baseline PD-1/PD-L1 levels are associated with further laboratory changes and/or shorter survival. Results: A total of 506 laboratory measurements from 37 metastatic CRC patients were analyzed. The baseline plasma PD-1 and PD-L1 levels were 27.73 ± 1.20 pg/mL and 16.01 ± 1.09 pg/mL, respectively. Disease progression (p = 0.0443) and baseline high-sensitivity C-reactive protein (p = 0.0011), aspartate transaminase (p = 0.0253), alanine transaminase (p = 0.0386), and gamma-glutamyl transferase (p = 0.0103) were associated with higher PD-L1 levels. Based on the baseline PD-1/PD-L1 levels, low and high PD-1/PD-L1 groups were created. Constant, pathological levels of complete blood count values, high-sensitivity C-reactive protein, serum albumin, high-density lipoprotein cholesterol, and lactate dehydrogenase were characteristic for patients with high baseline PD-L1. High PD-L1 levels were significantly associated with increased tumor burden. Disease-specific survival and progression-free survival were significantly shorter in patients with high PD-L1. Conclusions: Abnormal levels of laboratory parameters and intensified tumor burden can be expected if elevated baseline plasma PD-1/PD-L1 levels are found.

Prognostic significance of soluble PD-L1 in prostate cancer

“…Consistent with our findings, the association of sPD-L1 with disease advancement parameters has been identified in various other tumors: in aggressive bladder cancer ( 55 ), advanced (ccRCC) ( 12 ), and gastric cancer ( 35 ). Baseline sPD-L1 has proven to be a reliable tumor marker in metastatic breast cancer ( 48 ) and has been linked to rapid metastatic progression in metastatic ccRCC ( 51 ), as well as to the size of metastases in colorectal cancer ( 56 ). Elevated initial sPD-L1 levels have been associated with poorer prognosis in ccRCC ( 57 ), soft tissue sarcomas ( 28 ), pancreatic adenocarcinoma ( 58 ), lung cancer ( 49 , 59 ), hepatocellular carcinoma ( 36 ), and lower-grade glioma ( 40 ).…”

“…In metastatic ccRCC higher concentrations of sPD-1 tended to correlate with advanced cancer stage as well ( 51 ). For patients with metastatic colorectal cancer (mCRC), soluble PD-1, similar to soluble PD-L1, was linked to clinically worse levels of various peripheral blood parameters and metastatic tumor burden ( 56 ) and predicted systemic inflammation in pancreatic cancer ( 65 ). Although our data reflects finding between pretreatment sPD-1 levels and tumor progression in other cancers, the precise mechanism of the role of sPD-1 remains unclear.…”

“…Contrary, in other cancer studies it has been demonstrated that untreated cancer patients with elevated sPD-1 will have unfavorable survival outcomes ( 5 , 11 ). High sPD-1 concentrations predict reduced PFS duration in glioma ( 41 ) NSCLC ( 50 ) mCRC ( 56 ) and pancreatic adenocarcinoma ( 58 ). Poor survival in diffuse large B cell lymphoma was indicated by a correlation between high initial sPD-1 levels and the PD1+ T cells infiltrating the tumor ( 66 ).…”

Analysis of the Prognostic Potential of Schlafen 11, Programmed Death Ligand 1, and Redox Status in Colorectal Cancer Patients

“…In CRC, tumoral expression of the membrane-bound receptor form of PD-L1 (mPD-L1) is a rare characteristic strongly associated with PD-1-positive lymphocytic infiltrates and deficiency in mismatchrepair systems, which are markers predicting high immunogenicity and responsiveness to anti-PD-1/PD-L1 therapies [52]. However, a previous study by Dank et al showed that high levels of the PD-L1 soluble form (sPD-L1) in plasma were significantly associated with increased tumor burden and shorter disease-specific survival and progression-free survival in metastatic CRC patients [25]. Similarly, Omura et al confirmed the prognostic potential of both sPD-L1 and mPD-L1 in stage I-III CRC patients, where elevated pre-operative sPD-L1 levels were significantly correlated with lymphatic invasion, and both high tumoral mPD-L1 and elevated preoperative sPD-L1 were significantly associated with shorter overall survival and disease-free survival [24].…”

“…PD-L1 protein can also be found on malignant cells, providing an immune evasion mechanism exploited by different tumor types [23], including melanoma, non-small-cell lung cancer, ovarian and breast, and gastrointestinal malignancies. In CRC, determining the serum levels of PD-L1 may have prognostic significance since previous studies showed a negative correlation of PD-L1 serum levels in CRC patients with overall survival [24,25].…”