Soluble PD-L1 in NSCLC Patients Treated with Checkpoint Inhibitors and Its Correlation with Metabolic Parameters

Abstract

We investigated the role of soluble PD-L1 (sPD-L1) in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI) and analyzed its association with clinical outcomes and metabolic parameters by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). Between July 2017 and May 2019, we enrolled 20 candidate patients of ICI therapy who had serum frozen samples and 18F-FDG PET/CT available, both at baseline and at the first response evaluation. This analysis is embedded into a larger prospective study (NCT03563482). Twelve out of 20 patients received nivolumab, one patient received combination of nivolumab and ipilimumab, whereas the others received pembrolizumab. Median sPD-L1 level at baseline was 27.22 pg/mL. We found a significant association between patients with elevated sPD-L1, above the median value, and high metabolic tumor burden, expressed by metabolic tumor volume (MTV, 115.3 vs. 35.5, p = 0.034) and total lesion glycolysis (TLG, 687 vs. 210.1, p = 0.049). At the first restaging after 7–8 weeks, median sPD-L1 levels significantly increased as compared to baseline median value (43.9 pg/mL, p = 0.017). No significant differences in response rates were detected, according to both morphological and metabolic response criteria. Likewise, no difference in survival outcomes were observed between low sPD-L1 and high sPD-L1 patients. The increase of sPD-L1 concentrations during ICI treatment may reflect the expansion of tumor volume and the tumor lysis. Moreover, it is supposed that sPD-L1 has its own biological action, either by reducing membrane PD-1 sites available for nivolumab or by inducing lymphocytes exhaustion after binding their membrane PD-1. Further, larger studies are needed to confirm our preliminary results on the role of sPD-L1 during ICI therapy.

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

“…However, overall, the results are contrasted, and sPD-L1 alone does not appears as a sufficiently robust and reliable biomarker to predict outcome in most cases. In NSCLC, for example, some studies underlined that there is no difference in survival outcomes between low sPD-L1 and high sPD-L1 patients with NSCLC [ 123 ], whereas other studies indicated that plasma sPD-L1 (and sPD-L1/sPD-1 ratio) can be positively correlated with overall survival of NSCLC patients [ 126 ]. In parallel, other investigations concluded that exoPD-L1, but not sPD-L1, can be correlated with NSCLC disease progression [ 187 ].…”

“…Even in a defined cancer type and with a comparable method (ELISA), large differences of sPD-L1 levels have been reported, complicating the comparisons. For examples, in locally advanced non-small cell lung cancer (NSCLC), a median serum sPD-L1 concentration of 67–68 pg/mL has been reported [ 66 , 122 ], whereas other studies indicated median sPD-L1 levels of 27 pg/mL [ 123 ], 84 pg/mL [ 124 ] and 176 pg/mL [ 125 ]. Moreover, much higher values have been reported with other methods, up to 568 pg/mL measured using a multiplex assay [ 67 ] and 3.84 ng/mL measured with another ELISA procedure [ 126 ].…”

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients

“…In lung cancer, high levels of PDL1 are associated with poor prognosis, shorter OS and the presence of abdominal metastasis [ 16 , 30 ]. More recently, soluble PDL1 serum concentration has been associated with a high metabolic tumor burden, suggesting that the levels of PDL1 may reflect the expansion of tumor volume and tumor lysis during ICI treatment [ 31 ]. More discussed is the role of PD1 as a soluble form.…”

Positron Emission Tomography-Based Response to Target and Immunotherapies in Oncology

“…In conclusion, despite the more effective way of assessing the [ 18 F]FDG PET-based response in patients treated with ICPIs, available studies suggest that [ 18 F]FDG PET can support decision-making about the continuation/discontinuation of therapy, as it can open several windows able to capture different aspects associated with the effect of treatment (i.e., pseudoprogression, hyperprogression, and IRAE) [56]. Table 2 reports the characteristics of published studies involving the use of [ 18 F]FDG PET to assess the response to ICI [46][47][48]50,51,54,[57][58][59][60][61][62][63][64][65][66][67][68]. Figure 2 shows a representative example of baseline and post-treatment [ 18 F]FDG PET in a patient with advanced NSCLC treated with Nivolumab.…”

“…[ 68 Ga]DOTA-conjugate peptides (DOTA-TATE, DOTA-TOC, and DOTA-NOC) PET/CT are used to determine SSTR status (patients with SSTR-positive tumors are more likely to respond to targeted somatostatin analogue therapy), to predict therapeutic response to peptide receptor radionuclide therapy (PRRT) and to monitor the response to PRRT [80]. PRRT is successfully used to target metastatic or inoperable neuroendocrine tumors expressing subtype 2, leading to a longer survival and improved quality of life [81,82].…”