Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade

Abstract

Blockade of the pathway including Programmed death-ligand 1 (PD-L1) and its receptor Programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared to healthy donors. High pre-treatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors.

Immunoprofiles of colorectal cancer from Lynch syndrome

“…lymphoma and malignant melanoma. 32,33 This notion is supported by the fact that PD-L1 positive tumor-infiltrating immune cells, but not PD-L1 positive tumor cells, have been documented to predict prognosis, though its implication may vary according to tumor type. 34,35 In contrast to other types of cancer, such as melanoma, renal cell cancer and lung cancer, PD-L1 expression have not been able to predict response to anti-PD-1 therapy in MMR deficient colorectal cancers.…”

Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses

“…Additionally, the tolerogenicity linked with apoptosis is also augmented by some immunosuppressive cytokines (either secreted by the apoptotic cells or by the interacting immune cells), e.g. TGFβ, IL10, platelet‐activating factor, and PGE 2 ; or even secretion of soluble immune‐checkpoints like PD‐L1 . Last but not least, tolerogenic apoptosis can also directly inactivate potent DAMPs like HMGB1 via direct degradation through complement protease C1s or via oxidation facilitated by caspases …”

Biomarkers for immune checkpoint inhibitors: The importance of tumor topography and the challenges to cytopathology

“…Like the measurement of the tumor mutational burden, this method is attractive because it requires only a small amount of nucleic acids (messenger RNA) extracted from the tumor sample. Other alternative biomarkers of response include blood‐based biomarkers, such as assays for circulating (soluble) PD‐L1 . This method is unproven as a predictive biomarker but is attractive because it requires only peripheral blood.…”