Programmed Cell Death Ligand as a Biomarker for Response to Immunotherapy: Contribution of Mass Spectrometry-Based Analysis
Simple Summary
Abstract
1. Introduction
2. Discussion
2.1. PD-L1 Expression as Predictive Biomarker to ICIs Therapy
2.2. The Role of PD-L1 as Immune Checkpoint
2.3. PD-L1 as Predictive Biomarker in Response to ICIs Therapy
2.4. Assessment of PD-L1 Expression on Circulating Tumor Cells
2.5. MS-Based Analysis of PD-L1 Post-Translational Modifications
3. Some Predictive Biomarkers Under Investigation
3.1. Protein Tyrosine Phosphatase Receptor T (PTPRT) as a Potential Biomarker
3.2. Gut Microbiome Changes
4. Future Perspectives and Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ICIs | immune checkpoint inhibitors. |
PD-L1 | cell death ligand-L1 |
PD-1 | programmed cell death-1 |
CTLA-4 | cytotoxic T-lymphocyte antigen-4 |
LAG-3 | lymphocyte activation gene-3 |
NSCLC | non-small-cell lung cancer |
TMB | tumor mutational burden |
FDA | Food and Drug Administration |
dMMR | defective DNA mismatch repair |
MSI | microsatellite instability understudied |
PTMs | post-translational modifications |
LC-MS/MS | liquid chromatography-tandem mass spectrometry |
IHC | immunohistochemistry |
B2M | beta-2-microglobulin |
ESI | electrospray ionization |
EMA | European Medicines Agency |
CTCs | circulating tumor cells |
ctDNA | circulating tumor DNA |
PFS | progression-free survival |
mPFS | median progression-free survival |
DCR | disease control rate |
ES-SCLC | extensive-stage non-small-cell lung cancer |
DDA | data dependent acquisition mode |
IDO1 | indoleamine 2,3-dioxygenase 1 |
ELISA | enzyme-linked immunosorbent assay |
real-time PCR | real-time polymerase chain reaction |
qPCR | quantitative polymerase chain reaction |
PTPRT | protein tyrosine phosphatase receptor T |
cGAS | cyclic guanosine monophosphate–adenosine monophosphate synthase |
STAT3 | signal transducer and activator of transcription 3 |
2DE | two-dimensional gel electrophoresis (2DE) |
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FDA Approved Predictive Biomarkers | Some Potential Predictive Biomarkers Under Investigation. | Ref. |
---|---|---|
1. Programmed Death Ligand 1 (PD-L1) expression on tumor cells 2. Microsatellite Instability/Defective Mismatch Repair (MSI/dMMR) 3. Tumor Mutational Burden (TMB) | Gut microbiome. | [12] |
DNA damage response (DDR) gene alterations. | [19] | |
Targeting DNA damage response pathways in cancer | [20] | |
MHC-I genotypes. | [21] | |
beta-2-microglobulin (B2M) deficiency. | [22] | |
POLE mutations and JAK1/2 mutations. | [23,24] | |
Plasma biomarkers. | [25] | |
POLE/POLD1 mutations. | [26] | |
Loss of protein tyrosine phosphatase receptor type (PTPRT). | [27] |
Ref. | Investigated Disease | Method of Detection/ Sample | Conclusions/Comments |
---|---|---|---|
[51] | Advanced melanoma | Multiparametric flow cytometry Blood sample | A pilot study in which blood samples were collected from patients with metastatic melanoma receiving pembrolizumab (monoclonal antibody). Detectable PD-L1+CTCs were found in 64% of the patients. These patients had significantly longer progression-free survival (PFS) compared with patients with PD-L1− CTCs. |
[52] | Hepatocellular carcinoma Esophageal cancer Gastric cancer Neuroendocrine carcinoma Colorectal cancer Pancreatic cancer | Immunofluorescence Blood sample | One of the conclusions of this study is that high PD-L1 expression on CTCs could influence response in patients receiving PD-1/PD-L1 therapy. Patients with high PD-L1 expression prior to treatment had a higher response rate to the same therapy as well as longer progression-free survival (PFS) and overall survival (OS). |
[53] | Extensive-stage small-cell lung carcinoma (ES-SCLC). Limited-stage small cell lung carcinoma (LS-SCLC). | Immunofluorescence staining Blood and tissue samples. | Here, 43 patients were enrolled, 6 of them with ES-SCLC, 37 with LS-SCLC disease, and 10 healthy donors. This study concluded that correlation between samples derived from a limited number of ES-SCLC and LS-SCLC patients revealed a strong correlation between PD-1 expression on T-cells and PD-L1-expressing circulating CTCs. The same study reported that patients with high percentages of both CD3+CD8+PD-1+ T-cells and PD-L1+ CTCs had a survival advantage when treated with ICIs therapy. |
[54] | Advanced non-small-cell lung cancer (NSCLC) | Immunofluorescence/ immunohistochemical staining Blood and tissue samples | This study examined PD-L1 expression in tissue and on circulating CTCs from a limited number of NSCLC patients. The authors reported that circulating CTCs released a higher detection rate of PD-L1 expression than tumor tissues. Patients with PD-L1 expression on tissue or CTCs had a median progression-free survival (mPFS) significantly longer than those without PD-L1 detection. |
Protein | Type of PTM | Sites of Modification | Reference |
---|---|---|---|
PD-1 | N-linked glycosylation | N49, N58, N74, N116 | [57] |
Phosphorylation | S261 Y223, T248 | [58] | |
ubiquitination | K233 | [58,59,60] | |
O-linked glycosylation | T153, T168, S157, S159 | [61] | |
PD-L1 | N-linked glycosylation | N35, N192, N200, N219 | [62] |
Methylation | K75, K89, K105, R113, K162, R212 | [63] | |
phosphorylation | S176, T180, S184, S195, T210 | [64,65] | |
Acetylation | K263 | [66] |
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Agostini, M.; Traldi, P.; Hamdan, M. Programmed Cell Death Ligand as a Biomarker for Response to Immunotherapy: Contribution of Mass Spectrometry-Based Analysis. Cancers 2025, 17, 1001. https://doi.org/10.3390/cancers17061001
Agostini M, Traldi P, Hamdan M. Programmed Cell Death Ligand as a Biomarker for Response to Immunotherapy: Contribution of Mass Spectrometry-Based Analysis. Cancers. 2025; 17(6):1001. https://doi.org/10.3390/cancers17061001
Chicago/Turabian StyleAgostini, Marco, Pietro Traldi, and Mahmoud Hamdan. 2025. "Programmed Cell Death Ligand as a Biomarker for Response to Immunotherapy: Contribution of Mass Spectrometry-Based Analysis" Cancers 17, no. 6: 1001. https://doi.org/10.3390/cancers17061001
APA StyleAgostini, M., Traldi, P., & Hamdan, M. (2025). Programmed Cell Death Ligand as a Biomarker for Response to Immunotherapy: Contribution of Mass Spectrometry-Based Analysis. Cancers, 17(6), 1001. https://doi.org/10.3390/cancers17061001